Polymorphic forms of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one

ABSTRACT

Polymorphs of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, compositions thereof, methods for their preparation, and methods for their use are disclosed. Solvent forms of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, compositions thereof, methods for their preparation, and methods for their use are also disclosed.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of and priority to U.S. ProvisionalApplication Ser. No. 61/919,558, filed Dec. 20, 2013, the disclosure ofwhich is hereby incorporated by reference in its entirety.

FIELD

Provided are polymorphs of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,compositions thereof, methods for their preparation, and methods fortheir use. Also provided are solvate forms of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,compositions thereof; methods for their preparation, and methods fortheir use.

BACKGROUND

Cell signaling via 3′-phosphorylated phosphoinositides has beenimplicated in a variety of cellular processes, e.g., malignanttransformation, growth factor signaling, inflammation, and immunity. SeeRameh et al., J. Biol. Chem., 274:8347-8350 (1999) for a review. Theenzyme responsible for generating these phosphorylated signalingproducts is phosphatidylinositol 3-kinase (PI 3-kinase; PI3K). PI3Koriginally was identified as an activity associated with viraloncoproteins and growth factor receptor tyrosine kinases thatphosphorylates phosphatidylinositol (PI) and its phosphorylatedderivatives at the 3′-hydroxyl of the inositol ring. See Panayotou etal., Trends Cell Biol. 2:358-60 (1992).

Studies suggest that PI3K is involved in a range of cellular responsesincluding cell growth, differentiation, and apoptosis. See Parker etal., Curr. Biol., 5:577-99 (1995); Yao et al., Science, 267:2003-05(1995). PI3K also appears to be involved in a number of aspects ofleukocyte activation. See e.g., Pages et al., Nature, 369:327-29 (1994);Rudd, Immunity, 4:527-34 (1996); Fraser et al., Science, 251:313-16(1991).

Several compounds have been identified as PI3K inhibitors. For example,compounds capable of inhibiting the biological activity of human PI3K,including(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and their uses are disclosed in U.S. Pat. No. 6,518,277, U.S. Pat. No.6,667,300, and U.S. Pat. No. 7,932,260. Each of these references ishereby incorporated herein by reference in its entirety. In July 2014,ZYDELIG® (idelalisib), a first-in-class inhibitor of PI3K delta, wasapproved by the U.S. Food and Drug Administration for the treatment ofthree B-cell blood cancers. ZYDELIG® has also been approved by theEuropean Commission for two blood cancers, chronic lymphocytic leukemia(CLL) and follicular lymphoma (FL).

BRIEF SUMMARY

The present application provides a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, the hydrochloride saltof(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis substantially crystalline. In certain embodiments, the hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis crystalline. In certain embodiments, solvates of the hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneare provided.

In one aspect, provided herein are polymorphs of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and this compound has the following structure:

One or more of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX,X, XI, XII and XIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneare provided. In certain embodiments of the polymorphs provided herein,the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis a monohydrochloride salt.

These polymorphs can be characterized by a variety of solid stateanalytical data, including for example X-ray powder diffraction pattern(XRPD), differential scanning calorimetry (DSC), thermographic analysis(TGA), and Single Crystal X-Ray Crystallography. One of skill in the artwould recognize various techniques or methods that may be used togenerate such characterization data. Unless otherwise stated, the XRPDpatterns provided herein are generated by a powder X-ray diffractometerat room temperature. In certain instances, an XRPD pattern may also becalculated from the single crystal data acquired at 100K for thatpolymorphic form.

In another aspect, provided are compositions or pharmaceuticalcompositions comprising one or more polymorphic forms of a hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(including any one or more of polymorphic Forms I, II, III, IV, V, VI,VII, VIII, IX, X, XI, XII and XIII) and one or more pharmaceuticallyacceptable carriers or excipients. Provided are also articles ofmanufacture and unit dosage forms comprising any one or more of thepolymorphic forms of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(e.g., any one or more of polymorphic Forms I, II, III, IV, V, VI, VII,VIII, IX, X, XI, XII and XIII). Provided are also kits comprising anyone or more of the polymorphic forms (e.g., any one or more ofpolymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII andXIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one),and instructions for use (e.g., instructions for use in PI3K-mediateddisorder, such as cancer). In one embodiment of the pharmaceuticalcompositions, articles of manufacture, unit dosage forms, and kits, thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis a monohydrochloride salt.

Methods of using these polymorphic forms are provided. In anotheraspect, provided is a method of treating a human in need thereof,comprising administering to the human a polymorph of a hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one)(e.g., any one or more of polymorphic Forms I, II, III, IV, V, VI, VII,VIII, IX, X, XI, XII and XIII), or a composition (including apharmaceutical composition) comprising one or more such polymorphs. Thehuman may be in need of a treatment for cancer or an autoimmune disease.

In one variation, provided is a method of treating a PI3K-mediateddisorder in a human in need thereof, comprising administering to thehuman a polymorph of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one)(e.g., any one or more of polymorphic Forms I, II, III, IV, V, VI, VII,VIII, IX, X, XI, XII and XIII), or a composition (including apharmaceutical composition) comprising one or more such polymorphs. ThePI3K-mediated disorder, in some embodiments, is cancer (e.g., leukemiaor lymphoma) or an autoimmune disease.

Also provided is a method for increasing sensitivity of cancer cells tochemotherapy, comprising administering to a human undergoingchemotherapy with a chemotherapeutic agent an amount of a polymorph of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one)(e.g., any one or more of polymorphic Forms I, II, III, IV, V, VI, VII,VIII, IX, XI, XII and XIII), or a composition (including apharmaceutical composition) comprising one or more such polymorphs,sufficient to increase the sensitivity of cancer cells to thechemotherapeutic agent.

Also provided is a use of a polymorph of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one)(e.g., any one or more of polymorphic Forms I, II, III, IV, V, VI, VII,VIII, IX, X, XI, XII and XIII), or a composition (including apharmaceutical composition) comprising one or more such polymorphs, inthe manufacture of a medicament for the treatment of a diseaseresponsive to inhibition of PI3K activity, such as cancer (e.g.,leukemia or lymphoma) or an autoimmune disease.

In one embodiment of the methods of using, and the use of thepolymorphic forms described herein, the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis a monohydrochloride salt.

Methods of making these polymorphic forms are provided. In yet otheraspects, provided are methods of producing a composition comprising oneor more polymorphs of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one)(e.g., any one or more of polymorphic Forms I, II, III, IV, V, VI, VII,VIII, IX, X, XI, XII and XIII). The methods comprise combining ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one)with a suitable solvent or a suitable mixture of solvents. In oneembodiment, the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis a monohydrochloride salt. The solvent(S) may be selected from thegroup consisting of methanol, ethanol, water, isopropyl acetate, ethylacetate, methyl tert-butyl ether, n-heptane, acetonitrile, acetone,2-methyltetrahydrofuran, tetrahydrofuran, methyl isobutyl ketone, methylethyl ketone, dichloromethane, 2-propanol, 1-propanol, 1-butanol, andany mixtures thereof. Also provided are polymorphic products obtained bythe processes (e.g. methods of making) detailed herein.

In some embodiments, a solvate of a hydrochloride salt of a compound ofFormula (I) is provided:

In some embodiments, the solvate is selected from the group consistingof ethyl acetate, propyl acetate, 1-methyl-1-propanol, isopropylacetate, 1,2-dimethyoxyethane, 1,4-dioxane, acetone, acetone:water,acetonitrile, chloroform, dichloromethane, diethyl ether, ethyl acetate,MEK, MIBK, nitromethane, propyl acetate, tetrahydrofuran, toluene,1-propanol, 2-propanol, IPA:water (5%), and 2-methyl-1-propanol. In someembodiments, the solvate is selected from the group consisting of propylacetate, isopropyl acetate, 1,2-dimethyoxyethane, isopropyl alcohol,2-methyl-1-propanol, 1,4-dioxane, and toluene.

In some embodiments, the polymorph is selected from the group consistingof Pattern 1, Pattern 2, Pattern 3, Pattern 4, 2-Methyl-1-propanolsolvate, 1,4-Dioxane solvate, and Toluene solvate; and wherein:

-   -   Pattern 1 has an X-ray diffraction pattern comprising degree        2θ-reflections (±0.2 degrees 2θ) at 9.2, 23.4, 16.8, 18.5, and        25.8;    -   Pattern 2 has an X-ray diffraction pattern comprising degree        2θ-reflections (±0.2 degrees 2θ) at 7.8, 23.4, 9.2, 25.8, and        16.7;    -   Pattern 3 has an X-ray diffraction pattern comprising degree        2θ-reflections (±0.2 degrees 2θ) at 9.8, 21.5, 24.0, 11.7, and        19.7;    -   Pattern 4 has an X-ray diffraction pattern comprising degree        2θ-reflections (±0.2 degrees 2θ) at 12.3, 24.9, 16.8, 25.3, and        20.2;    -   2-Methyl-1-propanol solvate has an X-ray diffraction pattern        comprising degree 2θ-reflections (±0.2 degrees 2θ) at 8.6, 26.0,        17.3, 20.7, and 24.5;    -   1,4-Dioxane solvate has an X-ray diffraction pattern comprising        degree 2θ-reflections (±0.2 degrees 2θ) at 23.2, 18.8, 11.5,        19.4, and 21.1; and    -   Toluene solvate has an X-ray diffraction pattern comprising        degree 2θ-reflections (±0.2 degrees 2θ) at 25.5, 8.4, 23.3,        23.1, and 24.0.

DESCRIPTION OF THE FIGURES

The present disclosure can be best understood by references to thefollowing description taken in conjunction with the accompanyingfigures.

FIGS. 1A-1E show an X-ray powder diffraction pattern (XRPD) pattern, adifferential scanning calorimetry (DSC) graph, a thermographic analysis(TGA) graph, and two dynamic vapour sorption (DVS) graphs, respectively,of polymorphic Form I of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

FIG. 2 shows XRPD patterns of polymorphic Form II of a hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

FIG. 3 shows XRPD patterns of polymorphic Form III of a hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

FIG. 4 shows XRPD patterns of polymorphic Form IV of a hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

FIG. 5 shows XRPD patterns of polymorphic Form V of a hydrochloride saltof(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

FIG. 6 shows XRPD patterns of polymorphic Form VI of a hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

FIG. 7 shows XRPD patterns of polymorphic Form VII of a hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

FIG. 8 shows XRPD patterns of polymorphic Form VIII of a hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

FIG. 9 shows XRPD patterns of polymorphic Form IX of a hydrochloridesaltof(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

FIG. 10 shows XRPD patterns of polymorphic Form X of a hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

FIG. 11 shows XRPD patterns of polymorphic Form XI of a hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

FIG. 12 shows XRPD patterns of polymorphic Form XII of a hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

FIG. 13 shows XRPD patterns of polymorphic Form XIII of a hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

FIG. 14A shows XRPD Pattern 1 of a solvate form of a hydrochloride saltof(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(damp).

FIG. 14B shows XRPD Pattern 9 of a solvate form of a hydrochloride saltof(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

FIG. 14C shows XRPD Pattern 9′ of a solvate form of a hydrochloride saltof(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

FIG. 14D shows a differential scanning calorimetry (DSC) graph of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onerepresented as Pattern 9.

FIG. 14E shows a thermographic analysis (TGA) graph of a hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onerepresented as Pattern 9.

FIGS. 15A-15C show an X-ray powder diffraction pattern (XRPD) pattern, adifferential scanning calorimetry (DSC) graph, and a thermographicanalysis (TGA) graph of Pattern 2, a solvate of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

FIGS. 16A-16C show an X-ray powder diffraction pattern (XRPD) pattern, adifferential scanning calorimetry (DSC) graph, and a thermographicanalysis (TGA) graph of Pattern 3, a solvate of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

FIGS. 17A-17C show an X-ray powder diffraction pattern (XRPD) pattern, adifferential scanning calorimetry (DSC) graph, and a thermographicanalysis (TGA) graph of Pattern 4, a solvate of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

FIGS. 18A-18D show an X-ray powder diffraction pattern (XRPD) pattern, adifferential scanning calorimetry (DSC) graph, a thermographic analysis(TGA) graph, and an X-ray powder diffraction pattern (XRPD) pattern of a2-methyl-1-propanol solvate of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

FIGS. 19A-19C show an X-ray powder diffraction pattern (XRPD) pattern, adifferential scanning calorimetry (DSC) graph, and a thermographicanalysis (TGA) graph of a 1,4-dioxane solvate of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

FIG. 20 shows an X-ray powder diffraction pattern (XRPD) pattern of atoluene solvate of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

DETAILED DESCRIPTION

The following description is presented to enable a person of ordinaryskill in the art to make and use the various embodiments. Descriptionsof specific compounds, methods, techniques, and applications areprovided only as examples. Various modifications to the examplesdescribed herein will be readily apparent to those of ordinary skill inthe art, and the general principles described herein may be applied toother examples and applications without departing from the spirit andscope of the various embodiments. Thus, the various embodiments are notintended to be limited to the examples described herein and shown, butare to be accorded the scope consistent with the claims.

Terms used in the singular will also include the plural and vice versa.The use of the term “about” includes and describes the value orparameter per se. For example, “about x” includes and describes “x” perse. In some embodiments, the term “about” when used in association witha measurement, or used to modify a value, a unit, a constant, or a rangeof values, refers to variations of +/−5%.

Polymorphs of a Hydrochloride Salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one

A form of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onemay be present as an intermediate to the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,where a different polymorphic form or polymorphs may be beneficial forcertain purposes, such as medical or pharmaceutical uses.

It is desirable to develop a crystalline form of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,or a pharmaceutically acceptable salt thereof that is useful in thesynthesis of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.A form of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onemay be an intermediate to the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.A polymorphic form or polymorph has properties such as bioavailabilityand stability at certain conditions that are suitable for medical orpharmaceutical uses. By way of example, a crystalline form of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis an intermediate to an active agent or ingredient in a pharmaceuticalcomposition.

A crystalline form of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,or a pharmaceutically acceptable salt thereof; may provide the advantageof bioavailability and stability, suitable for use as an activeingredient in a pharmaceutical composition. Variations in the crystalstructure of a pharmaceutical drug substance or active ingredient mayaffect the dissolution rate (which may affect bioavailability, etc.),manufacturability (e.g., ease of handling, ability to consistentlyprepare doses of known strength) and stability (e.g., thermal stability,shelf life, etc.) of a pharmaceutical drug product or active ingredient.Such variations may affect the preparation or formulation ofpharmaceutical compositions in different dosage or delivery forms, suchas solid oral dosage form including tablets and capsules. Compared toother forms such as non-crystalline or amorphous forms, crystallineforms may provide desired or suitable hygroscopicity, particle sizecontrols, dissolution rate, solubility, purity, physical and chemicalstability, manufacturability, yield, and/or process control. Thus,crystalline forms of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,or a pharmaceutically acceptable salt thereof, provides advantage ofimproving the manufacturing process of an active agent or the stabilityor storability of a drug product form of the compound or an activeingredient, or having suitable bioavailability and/or stability as anactive agent.

The use of certain solvents has been found to produce differentpolymorphic forms of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,including any one or more of polymorphic Forms I to XIII, which mayexhibit one or more favorable characteristics described above. Theprocesses for the preparation of the polymorphs described herein, andcharacterization of these polymorphs are described in greater detailbelow.

One aspect of the application provides polymorphic forms of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,a compound having the molecular structure shown below:

In certain embodiments, the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis a monohydrochloride saltof(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, one or more of the polymorphic forms providedmay be a channel solvate. The crystal lattice of such polymorphic formsmay contain tunnels that penetrate the lattice, and the tunnels can beoccupied by one or more molecules (e.g., solvent molecules) and ions(e.g., chloride ions).

The compound name provided above is named using ChemBioDraw Ultra andone skilled in the art understands that the compound structure may benamed or identified using other commonly recognized nomenclature systemsand symbols. By way of example, the compound may be named or identifiedwith common names, systematic or non-systematic names. The nomenclaturesystems and symbols that are commonly recognized in the art of chemistryincluding but not limited to Chemical Abstract Service (CAS) andInternational Union of Pure and Applied Chemistry (IUPAC). Accordingly,the compound structure provided above may also be named or identified as5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]quinazolin-4(3H)-oneunder IUPAC and 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-4(3H)-quinazolinone under CAS.

Form I

In one aspect, provided is polymorphic Form I of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the polymorph exhibits an X-ray powder diffraction (XRPD)pattern substantially as shown in FIG. 1A. Polymorphic Form I mayexhibit a differential scanning calorimetry (DSC) thermogramsubstantially as shown in FIG. 1B. Polymorphic Form I may exhibit athermographic analysis (TGA) graph substantially as shown in FIG. 1C.Polymorphic Form I may exhibit dynamic vapour sorption (DVS) graphssubstantially as shown in FIGS. 1D and 1E.

The term “substantially as shown in” when referring, for example, to anXRPD pattern, a DSC thermogram, or a TGA graph includes a pattern,thermogram or graph that is not necessarily identical to those depictedherein, but that falls within the limits of experimental error ordeviations when considered by one of ordinary skill in the art.

Polymorphic Form I may have a unit cell as determined by crystal X-raycrystallography of the following dimensions: a=31.102 (15) Å; b=9.166(5) Å; c=19.738 (10) Å; α=90°; β=125.948 (17)°; and γ=90°.

In some embodiments of polymorphic Form I, at least one, at least two,at least three, at least four, at least five, at least six, at leastseven, at least eight, at least nine, at least ten, or all of thefollowing (a)-(k) apply: (a) polymorphic Form I has an XRPD patternsubstantially as shown in FIG. 1A; (b) polymorphic Form I has a DSCthermogram substantially as shown in FIG. 1B; (c) polymorphic Form I hasa TGA graph substantially as shown in FIG. IC; (d) polymorphic Form Ihas DVS graphs substantially as shown in FIGS. 1D and 1E; (e)polymorphic Form I has a unit cell, as determined by crystal X-raycrystallography, of the following dimensions: a=31.102 (15) Å; b=9.166(5) Å; c=19.738 (10) Å; α=90°; β=125.948 (17)°; and γ=90°; (f)polymorphic Form I has a melting temperature onset as determined by DSCat about 202° C.; (g) polymorphic Form I has a monoclinic crystalsystem; (h) polymorphic Form I has a C2 space group; (i) polymorphicForm I has a volume of 4555 (4) Å³; (j) polymorphic Form I has a Z valueof 8; and (k) polymorphic Form I has a density of 1.356 g/cm³.

In some embodiments, polymorphic Form I has at least one, at least two,at least three, or all of the following properties:

-   -   (a) an XRPD pattern substantially as shown in FIG. 1A;    -   (b) a DSC thermogram substantially as shown in FIG. 1B;    -   (c) DVS graphs substantially as shown in FIGS. 1D and/or 1E; and    -   (d) a unit cell, as determined by crystal X-ray crystallography,        of the following dimensions: a=31.102 (15) Å; b=9.166 (5) Å;        c=19.738 (10) Å; α=90°; β=125.948 (17)°; and γ=90°.

In some embodiments, polymorphic Form I has an XRPD pattern displayingat least two, at least three, at least four, at least five, or at leastsix of the degree 2θ-reflections with the greatest intensity as the XRPDpattern substantially as shown in FIG. 1A. It should be understood thatrelative intensities can vary depending on a number of factors,including sample preparation, mounting, and the instrument andanalytical procedure and settings used to obtain the spectrum. As such,the peak assignments listed herein, including for polymorphic Form I,are intended to encompass variations of +/−0.2 degrees 2θ.

In certain embodiments, polymorphic Form I has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.6, 16.6,18.2, 23.2 and 25.1. In one embodiment, polymorphic Form I has an XRPDpattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.6,16.6, 18.2, 23.2 and 25.1 and one or more of the degree 2θ-reflections(+/−0.2 degrees 2θ) at 8.9, 13.8, 19.4, and 22.5. In one embodiment,polymorphic Form I has an XRPD pattern comprising degree 2θ-reflections(+/−0.2 degrees 2θ) at 11.6, 16.6, 18.2, 23.2 and 25.1 and one of thedegree 2θ-reflections (+/−0.2 degrees 2θ) at 8.9, 13.8, 19.4, and 22.5.In one embodiment, polymorphic Form I has an XRPD pattern comprisingdegree 2θ-reflections (+/−0.2 degrees 2θ) at 11.6, 16.6, 18.2, 23.2 and25.1 and two of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.9,13.8, 19.4, and 22.5. In one embodiment, polymorphic Form I has an XRPDpattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.6,16.6, 18.2, 23.2 and 25.1 and three of the degree 2θ-reflections (+/−0.2degrees 2θ) at 8.9, 13.8, 19.4, and 22.5. In one embodiment, polymorphicForm I has an XRPD pattern comprising degree 2θ-reflections (+/−0.2degrees 2θ) at 8.9, 11.6, 13.8, 16.6, 18.2, 19.4, 22.5, 23.2 and 25.1.

In certain embodiments, the hydrochloride salt of polymorphic Form I isa monohydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In one embodiment, polymorphic Form I may be a channel solvate. Ascommonly referred to by a person skilled in the art, the term “channelsolvate”, or a variant thereof, refers to a crystal lattice containingtunnels that can be occupied by solvent molecules (e.g., channelsolvents), and other molecules and ions. Examples of other molecules andions that may be present in the channels of polymorphic Form I includewater, ethanol and/or chloride ions.

Form II

In another aspect, provided is polymorphic Form II of a hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the polymorph has a unit cell, as determined by Single CrystalX-Ray Crystallography, of the following dimensions: a=13.266 (3) Å;b=13.858 (3) Å; c=31.012 (6) Å; α=90°; β=90°; and γ=90°.

Polymorphic Form II may have a calculated XRPD pattern substantially asshown in FIG. 2. It should be understood that the XRPD provided in FIG.2 is a calculated XRPD from the single crystal data acquired at 100K forpolymorphic Form II.

In some embodiments of polymorphic Form II, at least one, at least two,at least three, at least four, at least five, at least six, or all ofthe following (a)-(g) apply: (a) polymorphic Form II has an XRPDpattern, calculated from the single crystal data acquired at 100K forpolymorphic Form II, substantially as shown in FIG. 2; (b) polymorphicForm II has a unit cell, as determined by Single Crystal X-RayCrystallography, of the following dimensions: a=13.266 (3) Å; b=13.858(3) Å; c=31.012 (6) Å; α=90°; β=90β; and γ=90°; (c) polymorphic Form IIhas an orthorhombic crystal system; (d) polymorphic Form II has a C222(1) space group; (e) polymorphic Form II has a volume of 5702 (2) Å³;(f) polymorphic Form II has a Z value of 8; and (g) polymorphic Form Ihas a density of 1.254 g/cm³.

In some embodiments, polymorphic Form II has at least one, or both ofthe following properties:

-   -   (a) an XRPD pattern, calculated from the single crystal data        acquired at 100K for polymorphic Form II, substantially as shown        in FIG. 2; and    -   (b) a unit cell, as determined by Single Crystal X-ray        Crystallography, of the following dimensions: a=13.266 (3) Å;        b=13.858 (3) Å; c=31.012 (6) Å; α=90°; β=90°; and γ=90°.

In some embodiments, polymorphic Form II has an XRPD pattern, calculatedfrom the single crystal data acquired at 100K for polymorphic Form II,displaying at least two, at least three, at least four, at least five,or at least six of the degree 2θ-reflections with the greatest intensityas the XRPD pattern substantially as shown in FIG. 2. It should beunderstood that relative intensities can vary depending on a number offactors, including sample preparation, mounting, and the instrument andanalytical procedure and settings used to obtain the spectrum. As such,the peak assignments disclosed herein, including for polymorphic FormII, are intended to encompass variations of +/−0.2 degrees 2θ.

In certain embodiments, the hydrochloride salt of polymorphic Form II isa monohydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

Form III

In another aspect, provided is polymorphic Form II of a hydrochloridesaltof(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the polymorph has a unit cell, as determined by Single CrystalX-Ray Crystallography, of the following dimensions: a=25.077 (3) Å;b=9.149 (10) Å; c=14.248 (14) Å; α=90°; β=110.967 (3)°; and γ=90°.

Polymorphic Form m may have a calculated XRPD pattern substantially asshown in FIG. 3. It should be understood that the XRPD provided in FIG.3 is a calculated XRPD from the single crystal data acquired at 100K forpolymorphic Form II.

In some embodiments of polymorphic Form III, at least one, at least two,at least three, at least four, or all of the following (a)-(e) apply:(a) polymorphic Form II has an XRPD pattern, calculated from the singlecrystal data acquired at 100K for polymorphic Form III, substantially asshown in FIG. 3; (b) polymorphic Form III has a unit cell, as determinedby Single Crystal X-Ray Crystallography, of the following dimensions:a=25.077 (3) Å; b=9.149 (10) Å; c=14.248 (14) Å; α=90°; β=110.967 (3)°;and γ=90°; (c) polymorphic Form III has an monoclinic crystal system;(d) polymorphic Form III has a C2 space group; and (e) polymorphic FormIII has a volume of 3052.2 (5) Å³.

In some embodiments, polymorphic Form III has at least one, or both ofthe following properties:

-   -   (a) an XRPD pattern, calculated from the single crystal data        acquired at 100K for polymorphic Form III, substantially as        shown in FIG. 3; and    -   (b) a unit cell, as determined by Single Crystal X-Ray        Crystallography, of the following dimensions: a=25.077 (3) Å;        b=9.149 (10) Å; c=14.248 (14) Å; α=90°; β=110.967 (3)°; and        γ=90°.

In some embodiments, polymorphic Form III has an XRPD pattern displayingat least two, at least three, at least four, at least five, or at leastsix of the degree 2θ-reflections with the greatest intensity as the XRPDpattern substantially as shown in FIG. 3. It should be understood thatrelative intensities can vary depending on a number of factors,including sample preparation, mounting, and the instrument andanalytical procedure and settings used to obtain the spectrum. As such,the peak assignments disclosed herein, including for polymorphic FormIII, are intended to encompass variations of +/−0.2 degrees 2θ.

In certain embodiments, the hydrochloride salt of polymorphic Form II isa monohydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In one embodiment, polymorphic Form III may have one or more channels.Such channels may be occupied by certain molecules and/or ions, such aswater and/or chloride ions.

Form IV

In another aspect, provided is polymorphic Form IV of a hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the polymorph has a unit cell, as determined by Single CrystalX-Ray Crystallography, of the following dimensions: a=13.469 (6) Å;b=13.842 (6) Å; c=31.754 (14) Å; α=90°; β=90°; and γ=90°.

Polymorphic Form IV may have a calculated XRPD pattern substantially asshown in FIG. 4. It should be understood that the XRPD provided in FIG.4 is a calculated XRPD from the single crystal data acquired at 100K forpolymorphic Form IV.

In some embodiments of polymorphic Form IV, at least one, at least two,at least three, at least four, at least five, at least six, at leastseven, or all of the following (a)-(h) apply: (a) polymorphic Form IVhas an XRPD pattern, calculated from the single crystal data acquired at100K for polymorphic Form IV, substantially as shown in FIG. 4; (b)polymorphic Form IV has a unit cell, as determined by Single CrystalX-Ray Crystallography, of the following dimensions: a=13.469 (6) Å;b=13.842 (6) Å; c=31.754 (14) Å; α=90°; β=90°; and γ=90°; (c)polymorphic Form IV has an orthorhombic crystal system; (d) polymorphicForm IV has a C222 (1) space group; (e) polymorphic Form IV has a volumeof 5919.8 (5) Å³; (f) polymorphic Form IV has a Z value of 8; (g)polymorphic Form IV has a density of 1.405 g/cm³; and (h) polymorphicForm IV has an absorption coefficient of 0.184 mm⁻¹.

In some embodiments, polymorphic Form IV has at least one, or both ofthe following properties:

-   -   (a) an XRPD pattern, calculated from the single crystal data        acquired at 100K for polymorphic Form IV, substantially as shown        in FIG. 4; and    -   (b) a unit cell, as determined by Single Crystal X-Ray        Crystallography, of the following dimensions: a=13.469 (6) Å;        b=13.842 (6) Å; c=31.754 (14) Å; α=90°; β=90°; and γ=90°.

In some embodiments, polymorphic Form IV has an XRPD pattern displayingat least two, at least three, at least four, at least five, or at leastsix of the degree 2θ-reflections with the greatest intensity as the XRPDpattern substantially as shown in FIG. 4. It should be understood thatrelative intensities can vary depending on a number of factors,including sample preparation, mounting, and the instrument andanalytical procedure and settings used to obtain the spectrum. As such,the peak assignments disclosed herein, including for polymorphic FormIV, are intended to encompass variations of +/−0.2 degrees 2θ.

In certain embodiments, the hydrochloride salt of polymorphic Form IV isa monohydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In one embodiment, polymorphic Form IV may have one or more channels.Such channels may be occupied by certain ions, such as chloride ions.

Form V

In another aspect, provided is polymorphic Form V of a hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the polymorph exhibits an XRPD pattern substantially as shown inFIG. 5.

In some embodiments, polymorphic Form V has an XRPD pattern displayingat least two, at least three, at least four, at least five, or at leastsix of the degree 2θ-reflections with the greatest intensity as the XRPDpattern substantially as shown in FIG. 5. It should be understood thatrelative intensities can vary depending on a number of factors,including sample preparation, mounting, and the instrument andanalytical procedure and settings used to obtain the spectrum. As such,the peak assignments listed herein, including for polymorphic Form V,are intended to encompass variations of +/−0.2 degrees 2θ.

In certain embodiments, polymorphic Form V has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 15.9, 24.0, 25.6and 28.1. In one embodiment, polymorphic Form V has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 15.9, 24.0,25.6, and 28.1 and one or more degree 2θ-reflections (+/−0.2 degrees 2θ)at 8.0, 18.9, 20.3, and 36.3. In one embodiment, polymorphic Form V hasan XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at15.9, 24.0, 25.6, and 28.1 and one degree 2θ-reflections (+/−0.2 degrees2θ) at 8.0, 18.9, 20.3, and 36.3. In one embodiment, polymorphic Form Vhas an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ)at 15.9, 24.0, 25.6, and 28.1 and two degree 2θ-reflections (+/−0.2degrees 2θ) at 8.0, 18.9, 20.3, and 36.3. In one embodiment, polymorphicForm V has an XRPD pattern comprising degree 2θ-reflections (+/−0.2degrees 2θ) at 15.9, 24.0, 25.6, and 28.1 and three degree2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 18.9, 20.3, and 36.3. In oneembodiment, polymorphic Form V has an XRPD pattern comprising degree2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 15.9, 18.9, 20.3, 24.0, 25.6,28.1 and 36.3.

Form VI

In another aspect, provided is polymorphic Form VI of a hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the polymorph exhibits an XRPD pattern substantially as shown inFIG. 6.

In some embodiments, polymorphic Form VI has an XRPD pattern displayingat least two, at least three, at least four, at least five, or at leastsix of the degree 2θ-reflections with the greatest intensity as the XRPDpattern substantially as shown in FIG. 6. It should be understood thatrelative intensities can vary depending on a number of factors,including sample preparation, mounting, and the instrument andanalytical procedure and settings used to obtain the spectrum. As such,the peak assignments listed herein, including for polymorphic Form VI,are intended to encompass variations of +/−0.2 degrees 2θ.

In certain embodiments, polymorphic Form VI has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.8, 17.0, 23.2and 25.1. In one embodiment, polymorphic Form VI has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 29) at 11.8, 13.9,16.7, 17.0, 19.9, 22.3, 22.5, 23.2 and 25.1 and one or more degree2θ-reflections (+/−0.2 degrees 2θ) at 13.9, 16.7, 19.9, 22.3, and 22.5.In one embodiment, polymorphic Form VI has an XRPD pattern comprisingdegree 2θ-reflections (+/−0.2 degrees 2θ) at 11.8, 13.9, 16.7, 17.0,19.9, 22.3, 22.5, 23.2 and 25.1 and one degree 2θ-reflections (+/−0.2degrees 2θ) at 13.9, 16.7, 19.9, 22.3, and 22.5. In one embodiment,polymorphic Form VI has an XRPD pattern comprising degree 2θ-reflections(+/−0.2 degrees 2θ) at 11.8, 13.9, 16.7, 17.0, 19.9, 22.3, 22.5, 23.2and 25.1 and two degree 2θ-reflections (+/−0.2 degrees 2θ) at 13.9,16.7, 19.9, 22.3, and 22.5. In one embodiment, polymorphic Form VI hasan XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at11.8, 13.9, 16.7, 17.0, 19.9, 22.3, 22.5, 23.2 and 25.1 and three degree2θ-reflections (+/−0.2 degrees 2θ) at 13.9, 16.7, 19.9, 22.3, and 22.5.In one embodiment, polymorphic Form VI has an XRPD pattern comprisingdegree 2θ-reflections (+/−0.2 degrees 2θ) at 11.8, 13.9, 16.7, 17.0,19.9, 22.3, 22.5, 232 and 25.1 and four degree 2θ-reflections (+/−0.2degrees 2θ) at 13.9, 16.7, 19.9, 22.3, and 22.5. In one embodiment,polymorphic Form VI has an XRPD pattern comprising degree 2θ-reflections(+/−0.2 degrees 2θ) at 11.8, 13.9, 16.7, 17.0, 19.9, 22.3, 22.5, 23.2and 25.1.

Form VII

In another aspect, provided is polymorphic Form VII of a hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the polymorph exhibits an XRPD pattern substantially as shown inFIG. 7.

In some embodiments, polymorphic Form VII has an XRPD pattern displayingat least two, at least three, at least four, at least five, or at leastsix of the degree 2θ-reflections with the greatest intensity as the XRPDpattern substantially as shown in FIG. 7. It should be understood thatrelative intensities can vary depending on a number of factors,including sample preparation, mounting, and the instrument andanalytical procedure and settings used to obtain the spectrum. As such,the peak assignments listed herein, including for polymorphic Form VII,are intended to encompass variations of +/−0.2 degrees 2θ.

In certain embodiments, polymorphic Form VII has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 17.8, 21.7and 24.0. In certain embodiments, polymorphic Form VII has an XRPDpattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8,11.9, 15.3, 19.7, 20.1, 21.7 and 24.0. In one embodiment, polymorphicForm VII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2degrees 2θ) at 9.8, 17.8, 21.7, and 24.0 and one or more degree2θ-reflections (+/−0.2 degrees 2θ) at 6.0, 11.9, 15.3, 19.7, 20.1, 28.4and 28.9. In one embodiment, polymorphic Form VII has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 17.8, 21.7and 24.0 and one degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.0, 11.9,15.3, 19.7, 20.1, 28.4 and 28.9. In one embodiment, polymorphic Form VIIhas an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ)at 9.8, 17.8, 21.7 and 24.0 and two degree 2θ-reflections (+/−0.2degrees 2θ) at 6.0, 11.9, 15.3, 19.7, 20.1, 28.4 and 28.9. In oneembodiment, polymorphic Form VII has an XRPD pattern comprising degree2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 17.8, 21.7 and 24.0 and threedegree 2θ-reflections (+/−0.2 degrees 2θ) at 6.0, 11.9, 15.3, 19.7,20.1, 28.4 and 28.9. In one embodiment, polymorphic Form VII has an XRPDpattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8,17.8, 21.7 and 24.0 and four degree 2θ-reflections (+/−0.2 degrees 2θ)at 6.0, 11.9, 15.3, 19.7, 20.1, 28.4 and 28.9. In one embodiment,polymorphic Form VII has an XRPD pattern comprising degree2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 17.8, 21.7 and 24.0 and fivedegree 2θ-reflections (+/−0.2 degrees 2θ) at 6.0, 11.9, 153, 19.7, 20.1,28.4 and 28.9. In one embodiment, polymorphic Form VII has an XRPDpattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8,17.8, 21.7 and 24.0 and six degree 2θ-reflections (+/−0.2 degrees 2θ) at6.0, 11.9, 15.3, 19.7, 20.1, 28.4 and 28.9. In one embodiment,polymorphic Form VII has an XRPD pattern comprising degree2θ-reflections (+/−0.2 degrees 2θ) at 6.0, 9.8, 11.9, 15.3, 19.7, 20.1,21.7, 24.0, 28.4 and 28.9.

Form VIII

In another aspect, provided is polymorphic Form VIII of a hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the polymorph exhibits an XRPD pattern substantially as shown inFIG. 8.

In some embodiments, polymorphic Form VIII has an XRPD patterndisplaying at least two, at least three, at least four, at least five,or at least six of the degree 2θ-reflections with the greatest intensityas the XRPD pattern substantially as shown in FIG. 8. It should beunderstood that relative intensities can vary depending on a number offactors, including sample preparation, mounting, and the instrument andanalytical procedure and settings used to obtain the spectrum. As such,the peak assignments listed herein, including for polymorphic Form VIII,are intended to encompass variations of +/−0.2 degrees 2θ.

In certain embodiments, polymorphic Form VIII has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 10.0, 19.9, 21.7and 24.1. In certain embodiments, polymorphic Form VIII has an XRPDpattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 10.0,12.4, 15.3, 20.3, 21.7 and 28.9. In one embodiment, polymorphic FormVIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2degrees 2θ) at 10.0, 19.9, 21.7 and 24.1 and one or more 2θ-reflections(+/−0.2 degrees 2θ) at 12.4, 15.3, 19.0, 20.3, and 28.9. In oneembodiment, polymorphic Form VIII has an XRPD pattern comprising degree2θ-reflections (+/−0.2 degrees 2θ) at 10.0, 19.9, 21.7 and 24.1 and one2θ-reflections (+/−0.2 degrees 2θ) at 12.4, 15.3, 19.0, 20.3, and 28.9.In one embodiment, polymorphic Form VIII has an XRPD pattern comprisingdegree 2θ-reflections (+/−0.2 degrees 2θ) at 10.0, 19.9, 21.7 and 24.1and two 2θ-reflections (+/−0.2 degrees 2θ) at 12.4, 15.3, 19.0, 20.3,and 28.9. In one embodiment, polymorphic Form VIII has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 10.0, 19.9, 21.7and 24.1 and three 2θ-reflections (+/−0.2 degrees 2θ) at 12.4, 15.3,19.0, 20.3, and 28.9. In one embodiment, polymorphic Form VIII has anXRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at10.0, 19.9, 21.7 and 24.1 and four 2θ-reflections (+/−0.2 degrees 2θ) at12.4, 15.3, 19.0, 20.3, and 28.9. In one embodiment, polymorphic FormVIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2degrees 2θ) at 10.0, 12.4, 15.3, 19.0, 19.9, 20.3, 21.7, 24.1 and 28.9.

Form IX

In another aspect, provided is polymorphic Form IX of a hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the polymorph exhibits an XRPD pattern substantially as shown inFIG. 9.

In some embodiments, polymorphic Form IX has an XRPD pattern displayingat least two, at least three, at least four, at least five, or at leastsix of the degree 2θ-reflections with the greatest intensity as the XRPDpattern substantially as shown in FIG. 9. It should be understood thatrelative intensities can vary depending on a number of factors,including sample preparation, mounting, and the instrument andanalytical procedure and settings used to obtain the spectrum. As such,the peak assignments listed herein, including for polymorphic Form IX,are intended to encompass variations of +/−0.2 degrees 2θ.

In certain embodiments, polymorphic Form IX has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 19.6, 21.8and 24.0. In certain embodiments, polymorphic Form IX has an XRPDpattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8,19.6, 21.8, 24.0 and 29.0. In one embodiment, polymorphic Form IX has anXRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at9.8, 19.6, 21.8 and 24.0 and one or more 2θ-reflections (+/−0.2 degrees2θ) at 9.5, 12.5, 20.8, and 29.0. In one embodiment, polymorphic Form IXhas an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ)at 9.8, 19.6, 21.8 and 24.0 and one 2θ-reflections (+/−0.2 degrees 2θ)at 9.5, 12.5, 20.8, and 29.0. In one embodiment, polymorphic Form IX hasan XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at9.8, 19.6, 21.8 and 24.0 and two 2θ-reflections (+/−0.2 degrees 2θ) at9.5, 12.5, 20.8, and 29.0. In one embodiment, polymorphic Form IX has anXRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at9.8, 19.6, 21.8 and 24.0 and three 2θ-reflections (+/−0.2 degrees 2θ) at9.5, 12.5, 20.8, and 29.0. In one embodiment, polymorphic Form IX has anXRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at9.5, 9.8, 12.5, 19.6, 20.8, 21.8, 24.0 and 29.0.

Form X

In another aspect, provided is polymorphic Form X of a hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the polymorph exhibits an XRPD pattern substantially as shown inFIG. 10.

In some embodiments, polymorphic Form X has an XRPD pattern displayingat least two, at least three, at least four, at least five, or at leastsix of the degree 2θ-reflections with the greatest intensity as the XRPDpattern substantially as shown in FIG. 10. It should be understood thatrelative intensities can vary depending on a number of factors,including sample preparation, mounting, and the instrument andanalytical procedure and settings used to obtain the spectrum. As such,the peak assignments listed herein, including for polymorphic Form X,are intended to encompass variations of +/−0.2 degrees 2θ.

In certain embodiments, polymorphic Form X has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.9, 21.8, and24.2. In certain embodiments, polymorphic Form X has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.9, 11.9, 15.5,21.8, 24.2, 28.6 and 29.0. In one embodiment, polymorphic Form X has anXRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at9.9, 21.8, and 24.2 and one or more degree 2θ-reflections (+/−0.2degrees 2θ) at 11.9, 15.5, 19.4, 19.8, 20.3, 28.6 and 29.0. In oneembodiment, polymorphic Form X has an XRPD pattern comprising degree2θ-reflections (+/−0.2 degrees 2θ) at 9.9, 21.8, and 24.2 and one degree2θ-reflections (+/−0.2 degrees 2θ) at 11.9, 15.5, 19.4, 19.8, 20.3, 28.6and 29.0. In one embodiment, polymorphic Form X has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.9, 21.8, and24.2 and two degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.9, 15.5,19.4, 19.8, 20.3, 28.6 and 29.0. In one embodiment, polymorphic Form Xhas an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ)at 9.9, 21.8, and 24.2 and three degree 2θ-reflections (+/−0.2 degrees2θ) at 11.9, 15.5, 19.4, 19.8, 20.3, 28.6 and 29.0. In one embodiment,polymorphic Form X has an XRPD pattern comprising degree 2θ-reflections(+/−0.2 degrees 2θ) at 9.9, 21.8, and 24.2 and four degree2θ-reflections (+/−0.2 degrees 2θ) at 11.9, 15.5, 19.4, 19.8, 20.3, 28.6and 29.0. In one embodiment, polymorphic Form X has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.9, 21.8, and24.2 and five degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.9, 15.5,19.4, 19.8, 20.3, 28.6 and 29.0. In one embodiment, polymorphic Form Xhas an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ)at 9.9, 21.8, and 24.2 and six degree 2θ-reflections (+/−0.2 degrees 2θ)at 11.9, 15.5, 19.4, 19.8, 20.3, 28.6 and 29.0. In one embodiment,polymorphic Form X has an XRPD pattern comprising degree 2θ-reflections(+/−0.2 degrees 2θ) at 9.9, 11.9, 15.5, 19.4, 19.8, 20.3, 21.8, 24.2,28.6 and 29.0.

Form XI

In another aspect, provided is polymorphic Form XI of a hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the polymorph exhibits an XRPD pattern substantially as shown inFIG. 11.

In some embodiments, polymorphic Form XI has an XRPD pattern displayingat least two, at least three, at least four, at least five, or at leastsix of the degree 2θ-reflections with the greatest intensity as the XRPDpattern substantially as shown in FIG. 11. It should be understood thatrelative intensities can vary depending on a number of factors,including sample preparation, mounting, and the instrument andanalytical procedure and settings used to obtain the spectrum. As such,the peak assignments listed herein, including for polymorphic Form XI,are intended to encompass variations of +/−0.2 degrees 2θ.

In certain embodiments, polymorphic Form XI has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 12.5, 17.0,19.3, 20.3, 22.0 and 25.5. In one embodiment, polymorphic Form XI has anXRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at12.5, 17.0, 19.3, 20.3, 22.0 and 25.5 and one or more degree2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 15.0, and 31.7. In oneembodiment, polymorphic Form XI has an XRPD pattern comprising degree2θ-reflections (+/−0.2 degrees 2θ) at 12.5, 17.0, 19.3, 20.3, 22.0 and25.5 and one degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 15.0, and31.7. In one embodiment, polymorphic Form XI has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 12.5, 17.0,19.3, 20.3, 22.0 and 25.5 and two degree 2θ-reflections (+/−0.2 degrees2θ) at 7.4, 15.0, and 31.7. In one embodiment, polymorphic Form XI hasan XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at7.4, 12.5, 15.0, 17.0, 19.3, 20.3, 22.0, 25.5 and 31.7.

Form XII

In another aspect, provided is polymorphic Form XII of a hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the polymorph exhibits an XRPD pattern substantially as shown inFIG. 12.

Polymorphic Form XII may have a unit cell as determined by crystal X-raycrystallography of the following dimensions: a=10.717 Å (3); b=10.161 Å(3); c=12.409 Å (4); α=90°; β=104.021° (4); and γ=90°.

In some embodiments, polymorphic Form XII has at least one, or both ofthe following properties:

-   -   (a) an XRPD pattern substantially as shown in FIG. 12; and    -   (b) a unit cell, as determined by Single Crystal X-Ray        Crystallography, of the following dimensions: a=10.717 Å (3);        b=10.161 Å (3); c=12.409 Å (4); α=90°; β=104.021° (4); and        γ=90°.

In some embodiments, polymorphic Form XII has an XRPD pattern displayingat least two, at least three, at least four, at least five, or at leastsix of the degree 2θ-reflections with the greatest intensity as the XRPDpattern substantially as shown in FIG. 12. It should be understood thatrelative intensities can vary depending on a number of factors,including sample preparation, mounting, and the instrument andanalytical procedure and settings used to obtain the spectrum. As such,the peak assignments listed herein, including for polymorphic Form XII,are intended to encompass variations of +/−0.2 degrees 2θ.

In certain embodiments, polymorphic Form XII has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 12.4, 16.9and 25.4. In one embodiment, polymorphic Form XII has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 12.4, 16.9and 25.4 and one or more degree 2θ-reflections (+/−0.2 degrees 2θ) at19.1, 19.6, 23.3, 24.9, and 29.4. In one embodiment, polymorphic FormXII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees2θ) at 7.4, 12.4, 16.9 and 25.4 and one degree 2θ-reflections (+/−0.2degrees 2θ) at 19.1, 19.6, 23.3, 24.9, and 29.4. In one embodiment,polymorphic Form XII has an XRPD pattern comprising degree2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 12.4, 16.9 and 25.4 and twodegree 2θ-reflections (+/−0.2 degrees 2θ) at 19.1, 19.6, 23.3, 24.9, and29.4. In one embodiment, polymorphic Form XII has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 12.4, 16.9and 25.4 and three degree 2θ-reflections (+/−0.2 degrees 2θ) at 19.1,19.6, 23.3, 24.9, and 29.4. In one embodiment, polymorphic Form XII hasan XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at7.4, 12.4, 16.9 and 25.4 and four degree 2θ-reflections (+/−0.2 degrees2θ) at 19.1, 19.6, 23.3, 24.9, and 29.4. In one embodiment, polymorphicForm XII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2degrees 2θ) at 7.4, 12.4, 16.9, 19.1, 19.6, 23.3, 24.9, 25.4 and 29.4.

In certain embodiments, the hydrochloride salt of polymorphic Form XIIis a monohydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In one embodiment, polymorphic Form XII may have one or more channels.

Form XIII

In another aspect, provided is polymorphic Form XIII of a hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the polymorph exhibits an XRPD pattern substantially as shown inFIG. 13.

In some embodiments, polymorphic Form XIII has an XRPD patterndisplaying at least two, at least three, at least four, at least five,or at least six of the degree 2θ-reflections with the greatest intensityas the XRPD pattern substantially as shown in FIG. 13. It should beunderstood that relative intensities can vary depending on a number offactors, including sample preparation, mounting, and the instrument andanalytical procedure and settings used to obtain the spectrum. As such,the peak assignments listed herein, including for polymorphic Form XIII,are intended to encompass variations of +/−0.2 degrees 2θ.

In certain embodiments, polymorphic Form XIII has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.9, 16.8, 18.5and 23.9. In one embodiment, polymorphic Form XIII has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.9, 16.8, 18.5and 23.9 and one or more degree 2θ-reflections (+/−0.2 degrees 2θ) at8.0, 8.1, 9.7, 11.7, 13.6, 23.5, and 25.7. In one embodiment,polymorphic Form XIII has an XRPD pattern comprising degree2θ-reflections (+/−0.2 degrees 2θ) at 6.9, 16.8, 18.5 and 23.9 and onedegree 2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 8.1, 9.7, 11.7, 13.6,23.5, and 25.7. In one embodiment, polymorphic Form XIII has an XRPDpattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.9,16.8, 18.5 and 23.9 and two degree 2θ-reflections (+/−0.2 degrees 2θ) at8.0, 8.1, 9.7, 11.7, 13.6, 23.5, and 25.7. In one embodiment,polymorphic Form XIII has an XRPD pattern comprising degree2θ-reflections (+/−0.2 degrees 2θ) at 6.9, 16.8, 18.5 and 23.9 and threedegree 2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 8.1, 9.7, 11.7, 13.6,23.5, and 25.7. In one embodiment, polymorphic Form XIII has an XRPDpattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.9,16.8, 18.5 and 23.9 and four degree 2θ-reflections (+/−0.2 degrees 2θ)at 8.0, 8.1, 9.7, 11.7, 13.6, 23.5, and 25.7. In one embodiment,polymorphic Form XIII has an XRPD pattern comprising degree2θ-reflections (+/−0.2 degrees 2θ) at 6.9, 16.8, 18.5 and 23.9 and fivedegree 2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 8.1, 9.7, 11.7, 13.6,23.5, and 25.7. In one embodiment, polymorphic Form XI has an XRPDpattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.9,16.8, 18.5 and 23.9 and six degree 2θ-reflections (+/−0.2 degrees 2θ) at8.0, 8.1, 9.7, 11.7, 13.6, 23.5, and 25.7. In one embodiment,polymorphic Form XIII has an XRPD pattern comprising degree2θ-reflections (+/−0.2 degrees 2θ) at 6.9, 8.0, 8.1, 9.7, 11.7, 13.6,16.8, 18.5, 23.5, 23.9 and 25.7.

In further embodiments, additional patterns of solvate forms of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneare provided.

Pattern 1

In one aspect, provided is Pattern 1 of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein Pattern 1 an X-ray powder diffraction (XRPD) patternsubstantially as shown in FIG. 14A.

In some embodiments, Pattern 1 has an XRPD pattern substantially asshown in FIG. 14A.

In some embodiments, Pattern 1 is a prepared in the presence ofpropylacetate. In some embodiments, Pattern 1 corresponds to apropylacetate solvate of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In some embodiments, Pattern 1 has an XRPD pattern displaying at leasttwo, at least three, at least four, at least five, or at least six ofthe degree 2θ-reflections with the greatest intensity as the XRPDpattern substantially as shown in FIG. 14A. It should be understood thatrelative intensities can vary depending on a number of factors,including sample preparation, mounting, and the instrument andanalytical procedure and settings used to obtain the spectrum. As such,the peak assignments listed herein, including for Pattern 1, areintended to encompass variations of +/−0.2 degrees 2θ.

In certain embodiments, Pattern 1 has an XRPD pattern comprising degree2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 23.4, 16.8, 18.5, and 25.8.In one embodiment, Pattern 1 has an XRPD pattern comprising degree2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 23.4, 16.8, 18.5, and 25.8and one or more of the degree 2θ-reflections (+/−0.2 degrees 2θ) at22.9, 11.7, 8.3, and 17.0. In one embodiment, Pattern 1 has an XRPDpattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.2,23.4, 16.8, 18.5, and 25.8 and one of the degree 2θ-reflections (+/−0.2degrees 2θ) at 22.9, 11.7, 8.3, and 17.0. In one embodiment, Pattern 1has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ)at 9.2, 23.4, 16.8, 18.5, and 25.8 and two of the degree 2θ-reflections(+/−0.2 degrees 2θ) at 22.9, 11.7, 8.3, and 17.0. In one embodiment,Pattern 1 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2degrees 2θ) at 9.2, 23.4, 16.8, 18.5, and 25.8 and three of the degree2θ-reflections (+/−0.2 degrees 2θ) at 22.9, 11.7, 8.3, and 17.0. In oneembodiment, Pattern 1 has an XRPD pattern comprising degree2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 23.4, 16.8, 18.5, 25.8, 22.9,11.7, 8.3, and 17.0. Table 1 shows the full XRPD peak list for Pattern1.

TABLE 1 XRPD Peak List for Pattern 1 Angle (2-Theta °) Intensity (%) 7.021.5 7.5 18.6 8.3 33.6 9.2 100.0 11.7 37.6 12.0 26.7 12.8 22.1 14.1 21.216.8 52.1 17.0 31.4 18.5 43.9 19.3 15.5 20.1 24.0 20.8 16.1 21.5 18.622.5 19.7 22.9 40.1 23.1 23.5 23.4 63.3 24.0 21.6 24.7 20.8 25.1 25.925.8 41.5 28.0 23.4 28.6 18.0

Pattern 9

In one aspect, provided is Pattern 9 of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein Pattern 9 an X-ray powder diffraction (XRPD) patternsubstantially as shown in FIG. 14B.

In some embodiments, Pattern 9 has an XRPD pattern substantially asshown in FIG. 14B.

In some embodiments, Pattern 9 is a prepared in the presence ofpropylacetate. In some embodiments, Pattern 9 corresponds to apropylacetate solvate of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In some embodiments, Pattern 9 has an XRPD pattern displaying at leasttwo, at least three, at least four, at least five, or at least six ofthe degree 2θ-reflections with the greatest intensity as the XRPDpattern substantially as shown in FIG. 14B. It should be understood thatrelative intensities can vary depending on a number of factors,including sample preparation, mounting, and the instrument andanalytical procedure and settings used to obtain the spectrum. As such,the peak assignments listed herein, including for Pattern 1, areintended to encompass variations of +/−0.2 degrees 2θ.

In certain embodiments, Pattern 9 has an XRPD pattern comprising degree2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 18.5, 25.8, 16.7, and 23.4.In one embodiment, Pattern 1 has an XRPD pattern comprising degree2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 18.5, 25.8, 16.7, and 23.4and one or more of the degree 2θ-reflections (+/−0.2 degrees 2θ) at27.9, 22.9, 14.0, and 17.0. In one embodiment, Pattern 9 has an XRPDpattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.2,18.5, 25.8, 16.7, and 23.4 and one of the degree 2θ-reflections (+/−0.2degrees 2θ) at 27.9, 22.9, 14.0, and 17.0. In one embodiment, Pattern 9has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ)at 9.2, 23.4, 16.8, 18.5, and 25.8 and two of the degree 2θ-reflections(+/−0.2 degrees 2θ) at 27.9, 22.9, 14.0, and 17.0. In one embodiment,Pattern 9 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2degrees 2θ) at 9.2, 18.5, 25.8, 16.7, and 23.4 and three of the degree2θ-reflections (+/−0.2 degrees 2θ) at 27.9, 22.9, 14.0, and 17.0. In oneembodiment, Pattern 9 has an XRPD pattern comprising degree2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 18.5, 25.8, 16.7, 23.4, 27.9,22.9, 14.0, and 17.0. Table 2 shows the full XRPD peak list for Pattern9.

TABLE 2 XRPD Peak List for Pattern 9 Angle (2-Theta °) Intensity (%) 6.96.3 7.5 11.4 8.3 8.9 9.2 100.0 11.7 13.8 12.0 9.4 12.8 4.7 14.0 15.816.7 29.0 17.0 14.7 17.7 4.5 18.5 31.5 19.3 6.0 20.1 7.3 20.8 10.4 21.47.6 22.6 12.9 22.9 18.9 23.4 27.9 23.9 7.1 24.8 9.5 25.1 8.5 25.8 30.127.9 19.7 28.5 9.6

Pattern 2

In one aspect, provided is Pattern 2 of the polymorphic Form I of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the polymorph exhibits an X-ray powder diffraction (XRPD)pattern substantially as shown in FIG. ISA. Pattern 2 may exhibit adifferential scanning calorimetry (DSC) thermogram substantially asshown in FIG. 15B. Pattern 2 may exhibit a thermographic analysis (TGA)graph substantially as shown in FIG. 15C.

In some embodiments, Pattern 2 is a prepared in the presence ofisopropyl acetate. In some embodiments, Pattern 2 corresponds to anisopropyl acetate solvate of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In some embodiments of Pattern 2, at least one, at least two, at leastthree, at least four, at least five, or all of the following (a)-(f)apply: (a) Pattern 2 has an XRPD pattern substantially as shown in FIG.15A; (b) Pattern 2 has a DSC thermogram substantially as shown in FIG.15B; (c) Pattern 2 has a TGA graph substantially as shown in FIG. 15C;(d) Form 2 has a melting temperature onset as determined by DSC at about68° C.; (e) Pattern 2 has a second melting temperature onset asdetermined by DSC at about 153° C.; and (f) Pattern 2 has a thirdmelting temperature onset as determined by DSC at about 179° C.

In some embodiments, Pattern 2 has at least one or both of the followingproperties:

-   -   (a) an XRPD pattern substantially as shown in FIG. 15A;    -   (b) a DSC thermogram substantially as shown in FIG. 15B;

In some embodiments, Pattern 2 has an XRPD pattern displaying at leasttwo, at least three, at least four, at least five, or at least six ofthe degree 2θ-reflections with the greatest intensity as the XRPDpattern substantially as shown in FIG. 15A. It should be understood thatrelative intensities can vary depending on a number of factors,including sample preparation, mounting, and the instrument andanalytical procedure and settings used to obtain the spectrum. As such,the peak assignments listed herein, including for Pattern 2, areintended to encompass variations of +/−0.2 degrees 2θ.

In certain embodiments, Pattern 2 has an XRPD pattern comprising degree26-reflections (+/−0.2 degrees 2θ) at 7.8, 23.4, 9.2, 25.8, and 16.7. Inone embodiment, Pattern 2 has an XRPD pattern comprising degree2θ-reflections (+/−0.2 degrees 2θ) at 7.8, 23.4, 9.2, 25.8, and 16.7 andone or more of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 22.8,25.0, 18.6, 13.3, and 28.1. In one embodiment, Pattern 2 has an XRPDpattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.8,23.4, 9.2, 25.8, and 16.7 and one of the degree 2θ-reflections (+/−0.2degrees 29) at 22.8, 25.0, 18.6, 13.3, and 28.1. In one embodiment,Pattern 2 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2degrees 2θ) at 7.8, 23.4, 9.2, 25.8, and 16.7 and two of the degree2θ-reflections (+/−0.2 degrees 2θ) at 22.8, 25.0, 18.6, 13.3, and 28.1.In one embodiment, Pattern 2 has an XRPD pattern comprising degree2θ-reflections (+/−0.2 degrees 2θ) at 7.8, 23.4, 9.2, 25.8, and 16.7 andthree of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 22.8, 25.0,18.6, 13.3, and 28.1. In one embodiment, Pattern 2 has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.8, 23.4, 9.2,25.8, 16.7, 22.8, 25.0, 18.6, 13.3, and 28.1. Table 3 shows the fullXRPD peak list for Pattern 2.

TABLE 3 XRPD Peak List for Pattern 2 Angle (2-Theta °) Intensity (%) 6.85.2 7.8 100.0 9.2 31.0 11.6 8.2 13.3 10.5 14.1 5.4 15.6 4.7 16.7 18.418.1 9.9 18.6 12.4 20.1 8.3 21.1 7.5 22.8 18.3 23.4 52.1 25.0 17.8 25.820.6 28.1 10.2

Pattern 3

In one aspect, provided is Pattern 3 of the polymorphic Form I of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluo-3-phenylquinazolin-4(3H)-one,wherein the polymorph exhibits an X-ray powder diffraction (XRPD)pattern substantially as shown in FIG. 16A. Pattern 3 may exhibit adifferential scanning calorimetry (DSC) thermogram substantially asshown in FIG. 16B. Pattern 3 may exhibit a thermographic analysis (TGA)graph substantially as shown in FIG. 16C.

In some embodiments, Pattern 3 is a prepared in the presence of1,2-dimethoxyethane. In some embodiments, Pattern 3 corresponds to an1,2-dimethoxyethane solvate of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In some embodiments of Pattern 3, at least one, at least two, at leastthree, or all of the following (a)-(d) apply: (a) Pattern 3 has an XRPDpattern substantially as shown in FIG. 16A; (b) Pattern 3 has a DSCthermogram substantially as shown in FIG. 16B; (c) Pattern 3 has a TGAgraph substantially as shown in FIG. 16C; and (d) Pattern 3 has amelting temperature onset as determined by DSC at about 172° C.

In some embodiments, Pattern 3 has at least one or both of the followingproperties:

-   -   (a) an XRPD pattern substantially as shown in FIG. 16A;    -   (b) a DSC thermogram substantially as shown in FIG. 16B;

In some embodiments, Pattern 3 has an XRPD pattern displaying at leasttwo, at least three, at least four, at least five, or at least six ofthe degree 2θ-reflections with the greatest intensity as the XRPDpattern substantially as shown in FIG. 16A. It should be understood thatrelative intensities can vary depending on a number of factors,including sample preparation, mounting, and the instrument andanalytical procedure and settings used to obtain the spectrum. As such,the peak assignments listed herein, including for Pattern 3, areintended to encompass variations of +/−0.2 degrees 2θ.

In certain embodiments, Pattern 3 has an XRPD pattern comprising degree2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 21.5, 24.0, 11.7, and 19.7.In one embodiment, Pattern 3 has an XRPD pattern comprising degree2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 21.5, 24.0, 11.7, and 19.7and one or more of the degree 2θ-reflections (+/−0.2 degrees 2θ) at20.0, 28.7, 15.1, 12.2, and 26.7. In one embodiment, Pattern 3 has anXRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at9.8, 21.5, 24.0, 11.7, and 19.7 and one of the degree 2θ-reflections(+/−0.2 degrees 2θ) at 20.0, 28.7, 15.1, 12.2, and 26.7. In oneembodiment, Pattern 3 has an XRPD pattern comprising degree2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 21.5, 24.0, 11.7, and 19.7and two of the degree 29-reflections (+/−0.2 degrees 2θ) at 20.0, 28.7,15.1, 12.2, and 26.7. In one embodiment, Pattern 3 has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 21.5, 24.0,11.7, and 19.7 and three of the degree 2θ-reflections (+/−0.2 degrees2θ) at 20.0, 28.7, 15.1, 12.2, and 26.7. In one embodiment, Pattern 3has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ)at 9.8, 21.5, 24.0, 11.7, 19.7, 20.0, 28.7, 15.1, 12.2, and 26.7. Table4 shows the full XRPD peak list for Pattern 3.

TABLE 4 XRPD Peak List for Pattern 3 Angle (2-Theta °) Intensity (%) 9.45.3 9.8 100.0 11.1 17.6 11.7 62.8 12.2 28.9 12.9 12.6 14.3 10.8 14.6 4.115.1 33.6 15.4 10.7 17.0 9.1 17.4 14.1 17.7 15.7 18.5 5.9 18.9 18.7 19.128.6 19.7 61.5 20.0 50.1 20.6 14.4 20.9 19.5 21.5 94.2 22.3 11.6 22.68.1 23.0 12.6 23.6 10.8 24.0 82.7 24.7 12.2 25.4 6.1 26.0 9.6 26.3 5.026.7 28.7 27.4 5.0 27.7 6.1 28.3 19.9 28.7 34.5 29.1 8.5 29.7 9.6

Pattern 4

In one aspect, provided is Pattern 4 of the polymorphic Form I of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the polymorph exhibits an X-ray powder diffraction (XRPD)pattern substantially as shown in FIG. 17A.

Pattern 4 may exhibit a differential scanning calorimetry (DSC)thermogram substantially as shown in FIG. 17B. Pattern 4 may exhibit athermographic analysis (TGA) graph substantially as shown in FIG. 17C.

In some embodiments, Pattern 4 is a prepared in the presence ofisopropyl alcohol. In some embodiments, Pattern 4 corresponds to anisopropyl alcohol solvate of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In some embodiments of Pattern 4, at least one, at least two, at leastthree, or all of the following (a)-(d) apply: (a) Pattern 4 has an XRPDpattern substantially as shown in FIG. 17A; (b) Pattern 4 has a DSCthermogram substantially as shown in FIG. 17B; (c) Pattern 4 has a TGAgraph substantially as shown in FIG. 17C; and (d) Pattern 4 has amelting temperature onset as determined by DSC at about 170° C.

In some embodiments, Pattern 4 has at least one or both of the followingproperties:

-   -   (a) an XRPD pattern substantially as shown in FIG. 17A;    -   (b) a DSC thermogram substantially as shown in FIG. 17B;

In some embodiments, Pattern 4 has an XRPD pattern displaying at leasttwo, at least three, at least four, at least five, or at least six ofthe degree 2θ-reflections with the greatest intensity as the XRPDpattern substantially as shown in FIG. 17A. It should be understood thatrelative intensities can vary depending on a number of factors,including sample preparation, mounting, and the instrument andanalytical procedure and settings used to obtain the spectrum. As such,the peak assignments listed herein, including for Pattern 4, areintended to encompass variations of +/−0.2 degrees 2θ.

In certain embodiments, Pattern 4 has an XRPD pattern comprising degree2θ-reflections (+/−0.2 degrees 2θ) at 12.3, 24.9, 16.8, 25.3, and 20.2.In one embodiment, Pattern 4 has an XRPD pattern comprising degree2θ-reflections (+/−0.2 degrees 2θ) at 12.3, 24.9, 16.8, 25.3, and 20.2and one or more of the degree 2θ-reflections (+/−0.2 degrees 2θ) at19.1, 21.8, 7.2, 14.8, and 19.6. In one embodiment, Pattern 4 has anXRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at12.3, 24.9, 16.8, 25.3, and 20.2 and one of the degree 2θ-reflections(+/−0.2 degrees 2θ) at 19.1, 21.8, 7.2, 14.8, and 19.6. In oneembodiment, Pattern 4 has an XRPD pattern comprising degree2θ-reflections (+/−0.2 degrees 2θ) at 12.3, 24.9, 16.8, 25.3, and 20.2and two of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 19.1, 21.8,7.2, 14.8, and 19.6. In one embodiment, Pattern 4 has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 12.3, 24.9,16.8, 25.3, and 20.2 and three of the degree 2θ-reflections (+/−0.2degrees 2θ) at 19.1, 21.8, 7.2, 14.8, and 19.6. In one embodiment,Pattern 4 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2degrees 2θ) at 12.3, 24.9, 16.8, 25.3, 20.2, 19.1, 21.8, 7.2, 14.8, and19.6. Table 5 shows the full XRPD peak list for Pattern 4.

TABLE 5 XRPD Peak List for Pattern 4 Angle (2-Theta °) Intensity (%) 7.213.8 8.4 3.1 11.4 7.0 12.3 100.0 13.0 5.1 14.5 3.4 14.8 11.3 15.2 2.616.8 58.7 17.3 1.8 17.7 7.9 18.5 3.2 18.8 4.4 19.1 18.9 19.6 11.3 19.99.1 20.2 24.2 20.5 9.7 21.3 7.7 21.8 18.5 23.0 11.3 23.5 6.0 24.0 6.324.5 2.8 24.9 70.9 25.3 42.0 25.7 4.2 26.4 3.6 26.8 6.1 27.4 1.8 27.84.7 28.0 10.3 28.3 2.2 29.1 4.2 29.5 6.6

2-Methyl-1-propanol Solvate

In one aspect, provided is the 2-methyl-1-propanol solvate form of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the polymorph exhibits an X-ray powder diffraction (XRPD)pattern substantially as shown in FIG. 18A. The 2-methyl-1-propanolsolvate may exhibit a differential scanning calorimetry (DSC) thermogramsubstantially as shown in FIG. 18B. The 2-methyl-1-propanol solvate mayexhibit a thermographic analysis (TGA) graph substantially as shown inFIG. 18C.

In some embodiments of the 2-methyl-1-propanol solvate, at least one, atleast two, at least three, or all of the following (a)-(d) apply: (a)2-methyl-1-propanol solvate has an XRPD pattern substantially as shownin FIG. 18A; (b) 2-methyl-1-propanol solvate has a DSC thermogramsubstantially as shown in FIG. 18B; (c) 2-methyl-1-propanol solvate hasa TGA graph substantially as shown in FIG. 18C; and (d)2-methyl-1-propanol solvate has a melting temperature onset asdetermined by DSC at about 113° C.

In some embodiments, the 2-methyl-1-propanol solvate has at least one orboth of the following properties:

-   -   (a) an XRPD pattern substantially as shown in FIG. 18A;    -   (b) a DSC thermogram substantially as shown in FIG. 18B;

In some embodiments, the 2-methyl-1-propanol solvate has an XRPD patterndisplaying at least two, at least three, at least four, at least five,or at least six of the degree 2θ-reflections with the greatest intensityas the XRPD pattern substantially as shown in FIG. 18A. It should beunderstood that relative intensities can vary depending on a number offactors, including sample preparation, mounting, and the instrument andanalytical procedure and settings used to obtain the spectrum. As such,the peak assignments listed herein, including for the2-methyl-1-propanol solvate, are intended to encompass variations of+/−0.2 degrees 2θ.

In certain embodiments, the 2-methyl-1-propanol solvate has an XRPDpattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.6,26.0, 17.3, 20.7, and 24.5. In one embodiment, the 2-methyl-1-propanolsolvate has an XRPD pattern comprising degree 2θ-reflections (+/−0.2degrees 2θ) at 8.6, 26.0, 17.3, 20.7, and 24.5 and one or more of thedegree 2θ-reflections (+/−0.2 degrees 2θ) at 24.3, 12.4, 22.5, 12.9, and28.5. In one embodiment, the 2-methyl-1-propanol solvate has an XRPDpattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.6,26.0, 17.3, 20.7, and 24.5 and one of the degree 2θ-reflections (+/−0.2degrees 2θ) at 24.3, 12.4, 22.5, 12.9, and 28.5. In one embodiment, the2-methyl-1-propanol solvate has an XRPD pattern comprising degree2θ-reflections (+/−0.2 degrees 2θ) at 8.6, 26.0, 17.3, 20.7, and 24.5and two of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 24.3, 12.4,22.5, 12.9, and 28.5. In one embodiment, the 2-methyl-1-propanol solvatehas an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ)at 8.6, 26.0, 17.3, 20.7, and 24.5 and three of the degree2θ-reflections (+/−0.2 degrees 2θ) at 24.3, 12.4, 22.5, 12.9, and 28.5.In one embodiment, the 2-methyl-1-propanol solvate has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.6, 26.0, 17.3,20.7, 24.5, 24.3, 12.4, 22.5, 12.9, and 28.5. Table 6 shows the fullXRPD peak list for the 2-methyl-1-propanol solvate.

TABLE 6 XRPD Peak List for 2-Methyl-1-propanol Solvate Form Angle(2-Theta °) Intensity (%) 4.3 2.9 5.9 1.0 8.6 100.0 9.9 0.7 10.3 3.211.2 1.2 12.1 2.6 12.4 3.8 12.7 1.1 12.9 3.3 13.8 2.8 14.1 0.6 14.6 0.515.4 0.9 16.0 1.6 16.9 3.0 17.3 18.5 17.7 3.0 17.9 0.9 18.5 0.7 18.9 2.719.4 0.6 19.9 1.8 20.2 2.7 20.5 2.8 20.7 4.8 20.9 2.9 21.9 1.4 22.5 3.422.8 3.2 23.7 1.4 23.9 1.9 24.3 4.1 24.5 4.7 24.8 2.9 25.4 1.7 26.0 60.226.9 1.2 27.6 1.7 28.0 1.4 28.3 2.6 28.5 3.3 28.8 3.3 29.6 1.0 29.8 1.1

1,4-Dioxane Solvate

In one aspect, provided is the 1,4-dioxane solvate form of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the polymorph exhibits an X-ray powder diffraction (XRPD)pattern substantially as shown in FIG. 19A. The 1,4-dioxane solvate mayexhibit a differential scanning calorimetry (DSC) thermogramsubstantially as shown in FIG. 19B. The 1,4-dioxane solvate may exhibita thermographic analysis (TGA) graph substantially as shown in FIG. 19C.

In some embodiments of the 1,4-dioxane solvate, at least one, at leasttwo, at least three, or all of the following (a)-(d) apply: (a)1,4-dioxane solvate has an XRPD pattern substantially as shown in FIG.19A; (b) 1,4-dioxane solvate has a DSC thermogram substantially as shownin FIG. 19B; (c) 1,4-dioxane solvate has a TGA graph substantially asshown in FIG. 19C; and (d) 1,4-dioxane solvate has a melting temperatureonset as determined by DSC at about 158° C.

In some embodiments, the 1,4-dioxane solvate has at least one or both ofthe following properties:

-   -   (a) an XRPD pattern substantially as shown in FIG. 19A;    -   (b) a DSC thermogram substantially as shown in FIG. 19B;

In some embodiments, the 1,4-dioxane solvate has an XRPD patterndisplaying at least two, at least three, at least four, at least five,or at least six of the degree 2θ-reflections with the greatest intensityas the XRPD pattern substantially as shown in FIG. 19A. It should beunderstood that relative intensities can vary depending on a number offactors, including sample preparation, mounting, and the instrument andanalytical procedure and settings used to obtain the spectrum. As such,the peak assignments listed herein, including for the 1,4-dioxanesolvate, are intended to encompass variations of +/−0.2 degrees 2θ.

In certain embodiments, the 1,4-dioxane solvate has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 23.2, 18.8,11.5, 19.4, and 21.1. In one embodiment, the 1,4-dioxane solvate has anXRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at23.2, 18.8, 11.5, 19.4, and 21.1 and one or more of the degree2θ-reflections (+/−0.2 degrees 2θ) at 20.6, 21.7, 11.9, 24.5, and 14.7.In one embodiment, the 1,4-dioxane solvate has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 23.2, 18.8,11.5, 19.4, and 21.1 and one of the degree 2θ-reflections (+/−0.2degrees 2θ) at 20.6, 21.7, 11.9, 24.5, and 14.7. In one embodiment, the1,4-dioxane solvate has an XRPD pattern comprising degree 2θ-reflections(+/−0.2 degrees 2θ) at 23.2, 18.8, 11.5, 19.4, and 21.1 and two of thedegree 2θ-reflections (+/−0.2 degrees 2θ) at 20.6, 21.7, 11.9, 24.5, and14.7. In one embodiment, the 1,4-dioxane solvate has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 23.2, 18.8,11.5, 19.4, and 21.1 and three of the degree 2θ-reflections (+/−0.2degrees 2θ) at 20.6, 21.7, 11.9, 24.5, and 14.7. In one embodiment, the1,4-dioxane solvate has an XRPD pattern comprising degree 2θ-reflections(+/−0.2 degrees 2θ) at 23.2, 18.8, 11.5, 19.4, 21.1, 20.6, 21.7, 11.9,24.5, and 14.7. Table 7 shows the full XRPD peak list for the1,4-dioxane solvate.

TABLE 7 XRPD Peak List for 1,4-Dioxane Solvate Form Angle (2-Theta °)Intensity (%) 6.9 13.6 8.0 6.1 9.6 4.9 11.5 78.6 11.9 26.1 12.7 10.213.7 8.7 14.7 20.5 15.1 4.9 16.2 19.4 16.9 13.5 17.5 5.4 17.7 6.2 18.16.4 18.8 83.1 19.4 62.8 19.8 12.5 20.6 49.0 21.1 60.0 21.7 36.3 22.7 9.823.2 100.0 24.1 9.1 24.5 22.2 25.2 4.8 25.6 10.4 26.0 15.0 26.3 5.2 26.65.5 27.2 8.9 27.7 5.6 28.4 7.4 28.7 7.1 29.3 4.7 29.6 6.1

Toluene Solvate

In one aspect, provided is a toluene solvent form of a hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the polymorph exhibits an X-ray powder diffraction (XRPD)pattern substantially as shown in FIG. 20.

In some embodiments of the toluene solvent form, the toluene solventform has an XRPD pattern substantially as shown in FIG. 20.

In some embodiments, the toluene solvent form has an XRPD patterndisplaying at least two, at least three, at least four, at least five,or at least six of the degree 2θ-reflections with the greatest intensityas the XRPD pattern substantially as shown in FIG. 20. It should beunderstood that relative intensities can vary depending on a number offactors, including sample preparation, mounting, and the instrument andanalytical procedure and settings used to obtain the spectrum. As such,the peak assignments listed herein, including for the toluene solventform, are intended to encompass variations of +/−0.2 degrees 2θ.

In certain embodiments the toluene solvent form has an XRPD patterncomprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 25.5, 8.4, 23.3,23.1, and 24.0. In one embodiment, the toluene solvent form has an XRPDpattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 25.5,8.4, 23.3, 23.1, and 24.0 and one or more of the degree 2θ-reflections(+/−0.2 degrees 2θ) at 16.6, 22.5, 27.9, 12.7, and 27.5. In oneembodiment, the toluene solvent form has an XRPD pattern comprisingdegree 2θ-reflections (+/−0.2 degrees 2θ) at 25.5, 8.4, 23.3, 23.1, and24.0 and one of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 16.6,22.5, 27.9, 12.7, and 27.5. In one embodiment the toluene solvent formhas an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ)at 25.5, 8.4, 23.3, 23.1, and 24.0 and two of the degree 2θ-reflections(+/−0.2 degrees 2θ) at 16.6, 22.5, 27.9, 12.7, and 27.5. In oneembodiment, the toluene solvent form has an XRPD pattern comprisingdegree 2θ-reflections (+/−0.2 degrees 2θ) at 25.5, 8.4, 23.3, 23.1, and24.0 and three of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 16.6,22.5, 27.9, 12.7, and 27.5. In one embodiment, the toluene solvent formhas an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ)at 25.5, 8.4, 23.3, 23.1, 24.0, 16.6, 22.5, 27.9, 12.7, and 27.5. Table8 shows the full XRPD peak list for the toluene solvent form.

TABLE 8 XRPD Peak List for Toluene Solvent Form Angle (2-Theta °)Intensity (%) 6.9 15.9 8.4 75.1 9.7 16.1 10.3 10.7 11.5 13.9 11.9 13.312.7 36.6 13.6 17.4 15.8 15.9 16.6 46.2 17.1 31.0 18.0 19.8 19.3 25.819.9 29.2 21.5 22.6 22.5 44.8 23.1 51.3 23.3 56.7 24.0 48.5 25.5 100.026.3 31.3 27.5 32.2 27.9 39.7 29.6 24.7Compositions Thereof

Provided are also compositions comprising at least one, at least two, atleast three, at least four, at least five, at least six, at least seven,at least eight, at least nine, at least ten, at least eleven, at leasttwelve, or all of polymorphs (e.g., any one or more of polymorphic FormsI, II, III, IV, V, VI, VII, VIII, IX, XI, XII and XIII) as describedherein. In a particular embodiment, a composition comprising one ofpolymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII andXIII described herein is provided. In a particular embodiment, acomposition comprising two of polymorphic Forms I, II, III, IV, V, VI,VII, VIII, IX, X, XI, XII and XIII described herein is provided. In aparticular embodiment, a composition comprising three of polymorphicForms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIIIdescribed herein is provided. In a particular embodiment, a compositioncomprising four of polymorphic Forms I, II, m, IV, V, VI, VII, VIII, IX,X, XI, XII and XIII described herein is provided. In a particularembodiment, a composition comprising five of polymorphic Forms I, II,III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII described herein isprovided. In a particular embodiment, a composition comprising six ofpolymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII andXIII described herein is provided. In a particular embodiment, acomposition comprising seven of polymorphic Forms I, II, III, IV, V, VI,VII, VIII, IX, X, XI, XII and XIII described herein is provided. In aparticular embodiment, a composition comprising eight of polymorphicForms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIIIdescribed herein is provided. In a particular embodiment, a compositioncomprising nine of polymorphic Forms I, II, III, IV, V, VI, VII, VIII,IX, X, XI, XII and XIII described herein is provided. In a particularembodiment, a composition comprising ten of polymorphic Forms I, II,III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII described herein isprovided. In a particular embodiment, a composition comprising eleven ofpolymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII andXIII described herein is provided. In a particular embodiment, acomposition comprising twelve of polymorphic Forms I, II, III, IV, V,VI, VII, VIII, IX, X, XI, XII and XIII described herein is provided. Inother embodiments, the compositions described herein may comprisesubstantially pure polymorphic forms, or may be substantially free ofother polymorphs and/or impurities.

In some embodiments, the term “substantially pure” or “substantiallyfree” with respect to a particular polymorphic form of a compound meansthat the composition comprising the polymorphic form contains less than95%, less than 90%, less than 80%, less than 70%, less than 65%, lessthan 60%, less than 55%, less than 50%, less than 40%, less than 30%,less than 20%, less than 15%, less than 10%, less than 5%, or less than1% by weight of other substances, including other polymorphic formsand/or impurities. In certain embodiments, “substantially pure” or“substantially free of” refers to a substance free of other substances,including other polymorphic forms and/or impurities. Impurities may, forexample, include by-products or left over reagents from chemicalreactions, contaminants, degradation products, other polymorphic forms,water, and solvents.

Form I

In some embodiments, the composition comprises polymorphic Form I of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments are provided compositions comprising polymorphicForm I as described herein, wherein the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewithin the composition is a substantially pure polymorphic Form I. Inparticular embodiments of compositions comprising polymorphic Form I, atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 85%, at least about 90%, at least about 95%, atleast about 96%, at least about 97%, at least about 98%, or at leastabout 99% of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition is polymorphic Form I. In certainembodiments, the composition includes at least about 50%, at least about60%, at least about 70%, at least about 80%, at least about 85%, atleast about 90%, at least about 95%, at least about 96%, at least about97%, at least about 98%, or at least about 99% of Form I of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In other embodiments of compositions comprising the polymorphic Form I,less than about 50%, less than about 40%, less than about 30%, less thanabout 20%, less than about 10%, less than about 5%, less than about 4%,less than about 3%, less than about 2% or less than about 1% of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition are other polymorphs of the hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(including, for example, polymorphic Forms II-XIII) and/or impurities.

In yet other embodiments of compositions comprising the polymorphic FormI, impurities make up less than about 5%, less than about 4%, less thanabout 3%, less than about 2% or less than about 1% of the total massrelative to the mass of the polymorphic Form I present. Impurities may,for example, include by-products from synthesizing the hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,contaminants, degradation products, other polymorphic forms, water, andsolvents. In certain embodiments, impurities include by-products fromthe process of synthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include contaminants from the processof synthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include degradation products of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include other polymorphic forms ofthe hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include water or solvent. In certainembodiments of compositions comprising the polymorphic Form I,impurities are selected from the group consisting of by-products fromsynthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,contaminants, degradation products, other polymorphic forms, water,solvents and combinations thereof.

In yet other embodiments, the composition comprising the polymorphicForm I has less than about 5%, less than about 4%, less than about 3%,less than about 2%, or less than about 1% by weight of amorphous ornon-crystalline hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In yet other embodiments, the composition comprising the polymorphicForm I has less than about 5%, less than about 4%, less than about 3%,less than about 2%, or less than about 1% by weight of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(e.g., in its free form).

Form II

In some embodiments, the composition comprises polymorphic Form II of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments are provided compositions comprising polymorphicForm II as described herein, wherein the hydrochloride saltof(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewithin the composition is a substantially pure polymorphic Form II. Inparticular embodiments of compositions comprising polymorphic Form II,at least about 50%, at least about 60%, at least about 70%, at leastabout 80%, at least about 85%, at least about 90%, at least about 95%,at least about 96%, at least about 97%, at least about 98%, or at leastabout 99% of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition is polymorphic Form II. In certainembodiments, the composition includes at least about 50%, at least about60%, at least about 70%, at least about 80%, at least about 85%, atleast about 90%, at least about 95%, at least about 96%, at least about97%, at least about 98%, or at least about 99% of Form II of thehydrochloride saltof(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In other embodiments of compositions comprising the polymorphic Form II,less than about 50%, less than about 40%, less than about 30%, less thanabout 20%, less than about 10%, less than about 5%, less than about 4%,less than about 3%, less than about 2% or less than about 1% of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition are other polymorphs of the hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(including, for example, polymorphic Forms I, III-XIII) and/orimpurities.

In yet other embodiments of compositions comprising the polymorphic FormII, impurities make up less than about 5%, less than about 4%, less thanabout 3%, less than about 2% or less than about 1% of the total massrelative to the mass of the polymorphic Form II present. Impurities may,for example, include by-products from synthesizing the hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,contaminants, degradation products, other polymorphic forms, water, andsolvents. In certain embodiments, impurities include by-products fromthe process of synthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include contaminants from the processof synthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include degradation products of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include other polymorphic forms ofthe hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include water or solvent. In certainembodiments of compositions comprising the polymorphic Form II,impurities are selected from the group consisting of by-products fromsynthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,contaminants, degradation products, other polymorphic forms, water,solvents and combinations thereof.

In certain embodiments of compositions comprising the polymorphic FormII, the compositions further comprise polymorphic Form X of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In other words, the compositions may comprise a mixture of polymorphicforms. In particular embodiments of compositions comprising a mixture ofpolymorphic Forms II and X, at least about 50%, at least about 60%, atleast about 70%, at least about 80%, at least about 85%, at least about90%, at least about 95%, at least about 96%, at least about 97%, atleast about 98%, or at least about 99% of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition are polymorphic Forms II and X. It should beunderstood that the relative ratio of polymorphic Form II to polymorphicForm X present in the composition may vary.

In yet other embodiments, the composition comprising the polymorphicForm II has less than about 5%, less than about 4%, less than about 3%,less than about 2%, or less than about 1% by weight of amorphous ornon-crystalline hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In yet other embodiments, the composition comprising the polymorphicForm II has less than about 5%, less than about 4%, less than about 3%,less than about 2%, or less than about 1% by weight of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(e.g., in its free form).

Form III

In some embodiments, the composition comprises polymorphic Form III of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments are provided compositions comprising polymorphicForm III as described herein, wherein the hydrochloride saltof(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewithin the composition is a substantially pure polymorphic Form III. Inparticular embodiments of compositions comprising polymorphic Form III,at least about 50%, at least about 60%, at least about 70%, at leastabout 80%, at least about 85%, at least about 90%, at least about 95%,at least about 96%, at least about 97%, at least about 98%, or at leastabout 99% of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition is polymorphic Form III. In certainembodiments, the composition includes at least about 50%, at least about60%, at least about 70%, at least about 80%, at least about 85%, atleast about 90%, at least about 95%, at least about 96%, at least about97%, at least about 98%, or at least about 99% of Form III of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In other embodiments of compositions comprising the polymorphic FormIII, less than about 50%, less than about 40%, less than about 30%, lessthan about 20%, less than about 10%, less than about 5%, less than about4%, less than about 3%, less than about 2% or less than about 1% of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition are other polymorphs of the hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(including, for example, polymorphic Forms I-II, IV-XIII) and/orimpurities.

In yet other embodiments of compositions comprising the polymorphic FormIII, impurities make up less than about 5%, less than about 4%, lessthan about 3%, less than about 2% or less than about 1% of the totalmass relative to the mass of the polymorphic Form II present. Impuritiesmay, for example, include by-products from synthesizing thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,contaminants, degradation products, other polymorphic forms, water, andsolvents. In certain embodiments, impurities include by-products fromthe process of synthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include contaminants from the processof synthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include degradation products of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include other polymorphic forms ofthe hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include water or solvent. In certainembodiments of compositions comprising the polymorphic Form II,impurities are selected from the group consisting of by-products fromsynthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,contaminants, degradation products, other polymorphic forms, water,solvents and combinations thereof.

In certain embodiments of compositions comprising the polymorphic FormIII, the compositions further comprise polymorphic Form V of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In other words, the compositions may comprise a mixture of polymorphicforms. In particular embodiments of compositions comprising a mixture ofpolymorphic Forms III and V, at least about 50%, at least about 60%, atleast about 70%, at least about 80%, at least about 85%, at least about90%, at least about 95%, at least about 96%, at least about 97%, atleast about 98%, or at least about 99% of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition are polymorphic Forms III and V. It should beunderstood that the relative ratio of polymorphic Form III topolymorphic Form V present in the composition may vary.

In yet other embodiments, the composition comprising the polymorphicForm III has less than about 5%, less than about 4%, less than about 3%,less than about 2%, or less than about 1% by weight of amorphous ornon-crystalline hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In yet other embodiments, the composition comprising the polymorphicForm III has less than about 5%, less than about 4%, less than about 3%,less than about 2%, or less than about 1% by weight of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(e.g., in its free form).

Form IV

In some embodiments, the composition comprises polymorphic Form IV of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments are provided compositions comprising polymorphicForm IV as described herein, wherein the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewithin the composition is a substantially pure polymorphic Form IV. Inparticular embodiments of compositions comprising polymorphic Form IV,at least about 50%, at least about 60%, at least about 70%, at leastabout 80%, at least about 85%, at least about 90%, at least about 95%,at least about 96%, at least about 97%, at least about 98%, or at leastabout 99% of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition is polymorphic Form IV. In certainembodiments, the composition includes at least about 50%, at least about60%, at least about 70%, at least about 80%, at least about 85%, atleast about 90%, at least about 95%, at least about 96%, at least about97%, at least about 98%, or at least about 99% of Form IV of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In other embodiments of compositions comprising the polymorphic Form IV,less than about 50%, less than about 40%, less than about 30%, less thanabout 20%, less than about 10%, less than about 5%, less than about 4%,less than about 3%, less than about 2% or less than about 1% of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition are other polymorphs of the hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(including, for example, polymorphic Forms I-III, V-XIII) and/orimpurities.

In yet other embodiments of compositions comprising the polymorphic FormIV, impurities make up less than about 5%, less than about 4%, less thanabout 3%, less than about 2% or less than about 1% of the total massrelative to the mass of the polymorphic Form IV present. Impurities may,for example, include by-products from synthesizing the hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,contaminants, degradation products, other polymorphic forms, water, andsolvents. In certain embodiments, impurities include by-products fromthe process of synthesizing the hydrochloride saltof(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include contaminants from the processof synthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include degradation products of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include other polymorphic forms ofthe hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include water or solvent. In certainembodiments of compositions comprising the polymorphic Form IV,impurities are selected from the group consisting of by-products fromsynthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,contaminants, degradation products, other polymorphic forms, water,solvents and combinations thereof.

In certain embodiments of compositions comprising the polymorphic FormIV, the compositions further comprise polymorphic Form IX of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In other words, the compositions may comprise a mixture of polymorphicforms. In particular embodiments of compositions comprising a mixture ofpolymorphic Forms IV and IX, at least about 50%, at least about 60%, atleast about 70%, at least about 80%, at least about 85%, at least about90%, at least about 95%, at least about 96%, at least about 97%, atleast about 98%, or at least about 99% of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition are polymorphic Forms IV and IX. It should beunderstood that the relative ratio of polymorphic Form IV to polymorphicForm IX present in the composition may vary.

In yet other embodiments, the composition comprising the polymorphicForm IV has less than about 5%, less than about 4%, less than about 3%,less than about 2%, or less than about 1% by weight of amorphous ornon-crystalline hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In yet other embodiments, the composition comprising the polymorphicForm IV has less than about 5%, less than about 4%, less than about 3%,less than about 2%, or less than about 1% by weight of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(e.g., in its free form).

Form V

In some embodiments, the composition comprises polymorphic Form V of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments are provided compositions comprising polymorphicForm V as described herein, wherein the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewithin the composition is a substantially pure polymorphic Form V. Inparticular embodiments of compositions comprising polymorphic Form V, atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 85%, at least about 90%, at least about 95%, atleast about 96%, at least about 97%, at least about 98%, or at leastabout 99% of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition is polymorphic Form V. In certainembodiments, the composition includes at least about 50%, at least about60%, at least about 70%, at least about 80%, at least about 85%, atleast about 90%, at least about 95%, at least about 96%, at least about97%, at least about 98%, or at least about 99% of Form V of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In other embodiments of compositions comprising the polymorphic Form V,less than about 50%, less than about 40%, less than about 30%, less thanabout 20%, less than about 10%, less than about 5%, less than about 4%,less than about 3%, less than about 2% or less than about 1% of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition are other polymorphs of the hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(including, for example, polymorphic Forms I-IV, VI-XIII) and/orimpurities.

In yet other embodiments of compositions comprising the polymorphic FormV, impurities make up less than about 5%, less than about 4%, less thanabout 3%, less than about 2% or less than about 1% of the total massrelative to the mass of the polymorphic Form V present. Impurities may,for example, include by-products from synthesizing the hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,contaminants, degradation products, other polymorphic forms, water, andsolvents. In certain embodiments, impurities include by-products fromthe process of synthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include contaminants from the processof synthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include degradation products of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include other polymorphic forms ofthe hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include water or solvent. In certainembodiments of compositions comprising the polymorphic Form V,impurities are selected from the group consisting of by-products fromsynthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,contaminants, degradation products, other polymorphic forms, water,solvents and combinations thereof.

In certain embodiments of compositions comprising the polymorphic FormV, the compositions further comprise polymorphic Form II of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In other words, the compositions may comprise a mixture of polymorphicforms. In particular embodiments of compositions comprising a mixture ofpolymorphic Forms III and V, at least about 50%, at least about 60%, atleast about 70%, at least about 80%, at least about 85%, at least about90%, at least about 95%, at least about 96%, at least about 97%, atleast about 98%, or at least about 99% of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition are polymorphic Forms III and V. It should beunderstood that the relative ratio of polymorphic Form III topolymorphic Form V present in the composition may vary.

In yet other embodiments, the composition comprising the polymorphicForm V has less than about 5%, less than about 4%, less than about 3%,less than about 2%, or less than about 1% by weight of amorphous ornon-crystalline hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In yet other embodiments, the composition comprising the polymorphicForm V has less than about 5%, less than about 4%, less than about 3%,less than about 2%, or less than about 1% by weight of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(e.g., in its free form).

Form VI

In some embodiments, the composition comprises polymorphic Form VI of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments are provided compositions comprising polymorphicForm VI as described herein, wherein the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewithin the composition is a substantially pure polymorphic Form VI. Inparticular embodiments of compositions comprising polymorphic Form VI,at least about 50%, at least about 60%, at least about 70%, at leastabout 80%, at least about 85%, at least about 90%, at least about 95%,at least about 96%, at least about 97%, at least about 98%, or at leastabout 99% of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition is polymorphic Form VI. In certainembodiments, the composition includes at least about 50%, at least about60%, at least about 70%, at least about 80%, at least about 85%, atleast about 90%, at least about 95%, at least about 96%, at least about97%, at least about 98%, or at least about 99% of Form VI of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In other embodiments of compositions comprising the polymorphic Form VI,less than about 50%, less than about 40%, less than about 30%, less thanabout 20%, less than about 10%, less than about 5%, less than about 4%,less than about 3%, less than about 2% or less than about 1% of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition are other polymorphs of the hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(including, for example, polymorphic Forms I-V, VII-XIII) and/orimpurities.

In yet other embodiments of compositions comprising the polymorphic FormVI, impurities make up less than about 5%, less than about 4%, less thanabout 3%, less than about 2% or less than about 1% of the total massrelative to the mass of the polymorphic Form VI present. Impurities may,for example, include by-products from synthesizing the hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,contaminants, degradation products, other polymorphic forms, water, andsolvents. In certain embodiments, impurities include by-products fromthe process of synthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include contaminants from the processof synthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include degradation products of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include other polymorphic forms ofthe hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include water or solvent. In certainembodiments of compositions comprising the polymorphic Form VI,impurities are selected from the group consisting of by-products fromsynthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,contaminants, degradation products, other polymorphic forms, water,solvents and combinations thereof.

In yet other embodiments, the composition comprising the polymorphicForm VI has less than about 5%, less than about 4%, less than about 3%,less than about 2%, or less than about 1% by weight of amorphous ornon-crystalline hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In yet other embodiments, the composition comprising the polymorphicForm VI has less than about 5%, less than about 4%, less than about 3%,less than about 2%, or less than about 1% by weight of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(e.g., in its free form).

Form VII

In some embodiments, the composition comprises polymorphic Form VII of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments are provided compositions comprising polymorphicForm VII as described herein, wherein the hydrochloride saltof(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewithin the composition is a substantially pure polymorphic Form VII. Inparticular embodiments of compositions comprising polymorphic Form VII,at least about 50%, at least about 60%, at least about 70%, at leastabout 80%, at least about 85%, at least about 90%, at least about 95%,at least about 96%, at least about 97%, at least about 98%, or at leastabout 99% of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition is polymorphic Form VII. In certainembodiments, the composition includes at least about 50%, at least about60%, at least about 70%, at least about 80%, at least about 85%, atleast about 90%, at least about 95%, at least about 96%, at least about97%, at least about 98%, or at least about 99% of Form VII of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In other embodiments of compositions comprising the polymorphic FormVII, less than about 50%, less than about 40%, less than about 30%, lessthan about 20%, less than about 10%, less than about 5%, less than about4%, less than about 3%, less than about 2% or less than about 1% of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition are other polymorphs of the hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(including, for example, polymorphic Forms I-VI, VIII-XIII) and/orimpurities.

In yet other embodiments of compositions comprising the polymorphic FormVII, impurities make up less than about 5%, less than about 4%, lessthan about 3%, less than about 2% or less than about 1% of the totalmass relative to the mass of the polymorphic Form VII present.Impurities may, for example, include by-products from synthesizing thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,contaminants, degradation products, other polymorphic forms, water, andsolvents. In certain embodiments, impurities include by-products fromthe process of synthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include contaminants from the processof synthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include degradation products of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include other polymorphic forms ofthe hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include water or solvent. In certainembodiments of compositions comprising the polymorphic Form VII,impurities are selected from the group consisting of by-products fromsynthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,contaminants, degradation products, other polymorphic forms, water,solvents and combinations thereof.

In yet other embodiments, the composition comprising the polymorphicForm VII has less than about 5%, less than about 4%, less than about 3%,less than about 2%, or less than about 1% by weight of amorphous ornon-crystalline hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In yet other embodiments, the composition comprising the polymorphicForm VII has less than about 5%, less than about 4%, less than about 3%,less than about 2%, or less than about 1% by weight of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(e.g., in its free form).

Form VIII

In some embodiments, the composition comprises polymorphic Form VIII ofa hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments are provided compositions comprising polymorphicForm VIII as described herein, wherein the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewithin the composition is a substantially pure polymorphic Form VIII. Inparticular embodiments of compositions comprising polymorphic Form VIII,at least about 50%, at least about 60%, at least about 70%, at leastabout 80%, at least about 85%, at least about 90%, at least about 95%,at least about 96%, at least about 97%, at least about 98%, or at leastabout 99% of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition is polymorphic Form VIII. In certainembodiments, the composition includes at least about 50%, at least about60%, at least about 70%, at least about 80%, at least about 85%, atleast about 90%, at least about 95%, at least about 96%, at least about97%, at least about 98%, or at least about 99% of Form VIII of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In other embodiments of compositions comprising the polymorphic FormVIII, less than about 50%, less than about 40%, less than about 30%,less than about 20%, less than about 10%, less than about 5%, less thanabout 4%, less than about 3%, less than about 2% or less than about 1%of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition are other polymorphs of the hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(including, for example, polymorphic Forms I-VII, IX-XIII) and/orimpurities.

In yet other embodiments of compositions comprising the polymorphic FormVIII, impurities make up less than about 5%, less than about 4%, lessthan about 3%, less than about 2% or less than about 1% of the totalmass relative to the mass of the polymorphic Form VIII present.Impurities may, for example, include by-products from synthesizing thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,contaminants, degradation products, other polymorphic forms, water, andsolvents. In certain embodiments, impurities include by-products fromthe process of synthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include contaminants from the processof synthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)one. In certain embodiments, impurities include degradation products ofthe hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include other polymorphic forms ofthe hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include water or solvent. In certainembodiments of compositions comprising the polymorphic Form VIII,impurities are selected from the group consisting of by-products fromsynthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,contaminants, degradation products, other polymorphic forms, water,solvents and combinations thereof.

In yet other embodiments, the composition comprising the polymorphicForm VIII has less than about 5%, less than about 4%, less than about3%, less than about 2%, or less than about 1% by weight of amorphous ornon-crystalline hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In yet other embodiments, the composition comprising the polymorphicForm VIII has less than about 5%, less than about 4%, less than about3%, less than about 2%, or less than about 1% by weight of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(e.g., in its free form).

Form IX

In some embodiments, the composition comprises polymorphic Form IX of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments are provided compositions comprising polymorphicForm IX as described herein, wherein the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewithin the composition is a substantially pure polymorphic Form IX. Inparticular embodiments of compositions comprising polymorphic Form IX,at least about 50%, at least about 60%, at least about 70%, at leastabout 80%, at least about 85%, at least about 90%, at least about 95%,at least about 96%, at least about 97%, at least about 98%, or at leastabout 99% of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition is polymorphic Form IX. In certainembodiments, the composition includes at least about 50%, at least about60%, at least about 70%, at least about 80%, at least about 85%, atleast about 90%, at least about 95%, at least about 96%, at least about97%, at least about 98%, or at least about 99% of Form IX of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In other embodiments of compositions comprising the polymorphic Form IX,less than about 50%, less than about 40%, less than about 30%, less thanabout 20%, less than about 10%, less than about 5%, less than about 4%,less than about 3%, less than about 2% or less than about 1% of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition are other polymorphs of the hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(including, for example, polymorphic Forms I-VIII, X-XIII) and/orimpurities.

In yet other embodiments of compositions comprising the polymorphic FormIX, impurities make up less than about 5%, less than about 4%, less thanabout 3%, less than about 2% or less than about 1% of the total massrelative to the mass of the polymorphic Form IX present. Impurities may,for example, include by-products from synthesizing the hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,contaminants, degradation products, other polymorphic forms, water, andsolvents. In certain embodiments, impurities include by-products fromthe process of synthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include contaminants from the processof synthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include degradation products of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include other polymorphic forms ofthe hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include water or solvent. In certainembodiments of compositions comprising the polymorphic Form IX,impurities are selected from the group consisting of by-products fromsynthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,contaminants, degradation products, other polymorphic forms, water,solvents and combinations thereof.

In certain embodiments of compositions comprising the polymorphic FormIX, the compositions further comprise polymorphic Form IV of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In other words, the compositions may comprise a mixture of polymorphicforms. In particular embodiments of compositions comprising a mixture ofpolymorphic Forms IV and IX, at least about 50%, at least about 60%, atleast about 70%, at least about 80%, at least about 85%, at least about90%, at least about 95%, at least about 96%, at least about 97%, atleast about 98%, or at least about 99% of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)one present in the composition are polymorphic Forms IV and IX. Itshould be understood that the relative ratio of polymorphic Form IV topolymorphic Form IX present in the composition may vary.

In yet other embodiments, the composition comprising the polymorphicForm IX has less than about 5%, less than about 40, less than about 3%,less than about 2%, or less than about 1% by weight of amorphous ornon-crystalline hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In yet other embodiments, the composition comprising the polymorphicForm IX has less than about 5%, less than about 4%, less than about 3%,less than about 2%, or less than about 1% by weight of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(e.g., in its free form).

Form X

In some embodiments, the composition comprises polymorphic Form X of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments are provided compositions comprising polymorphicForm X as described herein, wherein the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewithin the composition is a substantially pure polymorphic Form X. Inparticular embodiments of compositions comprising polymorphic Form X, atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 85%, at least about 90%, at least about 95%, atleast about 96%, at least about 97%, at least about 98%, or at leastabout 99% of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition is polymorphic Form X. In certainembodiments, the composition includes at least about 50%, at least about60%, at least about 70%, at least about 80%, at least about 85%, atleast about 90%, at least about 95%, at least about 96%, at least about97%, at least about 98%, or at least about 99% of Form X of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In other embodiments of compositions comprising the polymorphic Form X,less than about 50%, less than about 40%, less than about 30%, less thanabout 20%, less than about 10%, less than about 5%, less than about 4%,less than about 3%, less than about 2% or less than about 1% of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition are other polymorphs of the hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(including, for example, polymorphic Forms I-IX, XI-XII) and/orimpurities.

In yet other embodiments of compositions comprising the polymorphic FormX, impurities make up less than about 5%, less than about 4%, less thanabout 3%, less than about 2% or less than about 1% of the total massrelative to the mass of the polymorphic Form X present. Impurities may,for example, include by-products from synthesizing the hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,contaminants, degradation products, other polymorphic forms, water, andsolvents. In certain embodiments, impurities include by-products fromthe process of synthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include contaminants from the processof synthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include degradation products of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include other polymorphic forms ofthe hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include water or solvent. In certainembodiments of compositions comprising the polymorphic Form X,impurities are selected from the group consisting of by-products fromsynthesizing the hydrochloride salt of(8)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,contaminants, degradation products, other polymorphic forms, water,solvents and combinations thereof.

In certain embodiments of compositions comprising the polymorphic FormX, the compositions further comprise polymorphic Form II of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In other words, the compositions may comprise a mixture of polymorphicforms. In particular embodiments of compositions comprising a mixture ofpolymorphic Forms II and X, at least about 50%, at least about 60%, atleast about 70%, at least about 80%, at least about 85%, at least about90%, at least about 95%, at least about 96%, at least about 97%, atleast about 98%, or at least about 99% of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition are polymorphic Forms II and X. It should beunderstood that the relative ratio of polymorphic Form II to polymorphicForm X present in the composition may vary.

In yet other embodiments, the composition comprising the polymorphicForm X has less than about 5%, less than about 4%, less than about 3%,less than about 2%, or less than about 1% by weight of amorphous ornon-crystalline hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In yet other embodiments, the composition comprising the polymorphicForm X has less than about 5%, less than about 4%, less than about 3%,less than about 2%, or less than about 1% by weight of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(e.g., in its free form).

Form XI

In some embodiments, the composition comprises polymorphic Form XI of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments are provided compositions comprising polymorphicForm XI as described herein, wherein the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewithin the composition is a substantially pure polymorphic Form XI. Inparticular embodiments of compositions comprising polymorphic Form XI,at least about 50%, at least about 60%, at least about 70%, at leastabout 80%, at least about 85%, at least about 90%, at least about 95%,at least about 96%, at least about 97%, at least about 98%, or at leastabout 99% of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition is polymorphic Form XI. In certainembodiments, the composition includes at least about 50%, at least about60%, at least about 70%, at least about 80%, at least about 85%, atleast about 90%, at least about 95%, at least about 96%, at least about97%, at least about 98%, or at least about 99% of Form XI of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)one.

In other embodiments of compositions comprising the polymorphic Form XI,less than about 50%, less than about 40%, less than about 30%, less thanabout 20%, less than about 10%, less than about 5%, less than about 4%,less than about 3%, less than about 2% or less than about 1% of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition are other polymorphs of the hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(including, for example, polymorphic Forms I-X, XII-XIII) and/orimpurities.

In yet other embodiments of compositions comprising the polymorphic FormXI, impurities make up less than about 5%, less than about 4%, less thanabout 3%, less than about 2% or less than about 1% of the total massrelative to the mass of the polymorphic Form XI present. Impurities may,for example, include by-products from synthesizing the hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,contaminants, degradation products, other polymorphic forms, water, andsolvents. In certain embodiments, impurities include by-products fromthe process of synthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include contaminants from the processof synthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include degradation products of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include other polymorphic forms ofthe hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include water or solvent. In certainembodiments of compositions comprising the polymorphic Form XI,impurities are selected from the group consisting of by-products fromsynthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,contaminants, degradation products, other polymorphic forms, water,solvents and combinations thereof.

In yet other embodiments, the composition comprising the polymorphicForm XI has less than about 5%, less than about 4%, less than about 3%,less than about 2%, or less than about 1% by weight of amorphous ornon-crystalline hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In yet other embodiments, the composition comprising the polymorphicForm XI has less than about 5%, less than about 4%, less than about 3%,less than about 2%, or less than about 1% by weight of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(e.g., in its free form).

Form XII

In some embodiments, the composition comprises polymorphic Form XII of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments are provided compositions comprising polymorphicForm XII as described herein, wherein the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewithin the composition is a substantially pure polymorphic Form XII. Inparticular embodiments of compositions comprising polymorphic Form XII,at least about 50%, at least about 60%, at least about 70%, at leastabout 80%, at least about 85%, at least about 90%, at least about 95%,at least about 96%, at least about 97%, at least about 98%, or at leastabout 99% of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition is polymorphic Form XII. In certainembodiments, the composition includes at least about 50%, at least about60%, at least about 70%, at least about 80%, at least about 85%, atleast about 90%, at least about 95%, at least about 96%, at least about97%, at least about 98%, or at least about 99% of Form XII of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluo-3-phenylquinazolin-4(3H)-one.

In other embodiments of compositions comprising the polymorphic FormXII, less than about 50%, less than about 40%, less than about 30%, lessthan about 20%, less than about 10%, less than about 5%, less than about4%, less than about 3%, less than about 2% or less than about 1% of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition are other polymorphs of the hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(including, for example, polymorphic Forms I-XI, XIII) and/orimpurities.

In yet other embodiments of compositions comprising the polymorphic FormXII, impurities make up less than about 5%, less than about 4%, lessthan about 3%, less than about 2% or less than about 1% of the totalmass relative to the mass of the polymorphic Form XII present.Impurities may, for example, include by-products from synthesizing thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,contaminants, degradation products, other polymorphic forms, water, andsolvents. In certain embodiments, impurities include by-products fromthe process of synthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include contaminants from the processof synthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include degradation products of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include other polymorphic forms ofthe hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include water or solvent. In certainembodiments of compositions comprising the polymorphic Form XII,impurities are selected from the group consisting of by-products fromsynthesizing the hydrochloride saltof(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,contaminants, degradation products, other polymorphic forms, water,solvents and combinations thereof.

In yet other embodiments, the composition comprising the polymorphicForm XII has less than about 5%, less than about 4%, less than about 3%,less than about 2%, or less than about 1% by weight of amorphous ornon-crystalline hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In yet other embodiments, the composition comprising the polymorphicForm XII has less than about 5%, less than about 4%, less than about 3%,less than about 2%, or less than about 1% by weight of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(e.g., in its free form).

Form XII

In some embodiments, the composition comprises polymorphic Form XIII ofa hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments are provided compositions comprising polymorphicForm XIII as described herein, wherein the hydrochloride saltof(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewithin the composition is a substantially pure polymorphic Form XIII. Inparticular embodiments of compositions comprising polymorphic Form XIII,at least about 50%, at least about 60%, at least about 70%, at leastabout 80%, at least about 85%, at least about 90%, at least about 95%,at least about 96%, at least about 97%, at least about 98%, or at leastabout 99% of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition is polymorphic Form XIII. In certainembodiments, the composition includes at least about 50%, at least about60%, at least about 70%, at least about 80%, at least about 85%, atleast about 90%, at least about 95%, at least about 96%, at least about97%, at least about 98%, or at least about 99% of Form XIII of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In other embodiments of compositions comprising the polymorphic FormXIII, less than about 50%, less than about 40%, less than about 30%,less than about 20%, less than about 10%, less than about 5%, less thanabout 4%, less than about 3%, less than about 2% or less than about 1%of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onepresent in the composition are other polymorphs of the hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-(3)-one(including, for example, polymorphic Forms I-XII) and/or impurities.

In yet other embodiments of compositions comprising the polymorphic FormXIII, impurities make up less than about 5%, less than about 4%, lessthan about 3%, less than about 2% or less than about 1% of the totalmass relative to the mass of the polymorphic Form XIII present.Impurities may, for example, include by-products from synthesizing thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,contaminants, degradation products, other polymorphic forms, water, andsolvents. In certain embodiments, impurities include by-products fromthe process of synthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include contaminants from the processof synthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include degradation products of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include other polymorphic forms ofthe hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In certain embodiments, impurities include water or solvent. In certainembodiments of compositions comprising the polymorphic Form XIII,impurities are selected from the group consisting of by-products fromsynthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,contaminants, degradation products, other polymorphic forms, water,solvents and combinations thereof.

In yet other embodiments, the composition comprising the polymorphicForm XIII has less than about 5%, less than about 4%, less than about3%, less than about 2%, or less than about 1% by weight of amorphous ornon-crystalline hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In yet other embodiments, the composition comprising the polymorphicForm XIII has less than about 5%, less than about 4%, less than about3%, less than about 2%, or less than about 1% by weight of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(e.g., in its free form).

Preparation of the Polymorphs

One method of synthesizing(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onehas been previously described in U.S. Pat. No. 7,932,260. This referenceis hereby incorporated herein by reference in its entirety, andspecifically with respect to the synthesis of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.One or more polymorphic forms of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onemay be prepared from(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneor from its hydrochloride salt.

For example, in one aspect, provided is a method of producing acomposition comprising one or more polymorphs of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the method comprises combining a compound of Formula (I) withhydrochloric acid and a suitable solvent or a mixture of suitablesolvents to produce a composition comprising one or more polymorphs ofthe hydrochloride salt of the compound of Formula (I). In anotheraspect, provided is another method of producing a composition comprisingone or more polymorphs of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the method comprises combining a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith a suitable solvent or a mixture of suitable solvents.

The choice of a particular solvent or combination of solvents affectsthe formation favoring one polymorphic form of a hydrochloride salt(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneover another. Solvents suitable for polymorph formation may include, forexample, methanol, ethanol, water, isopropyl acetate, ethyl acetate,methyl tert-butyl ether, n-heptane, acetonitrile, acetone,2-methyltetrahydrofuran, tetrahydrofuran, methyl isobutyl ketone, methylethyl ketone, dichloromethane, 2-propanol, 1-propanol, 1-butanol, andany mixtures thereof.

In another aspect, provided is also one or more polymorphs of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneproduced according to any of the methods described herein.

It should be understood that the methods for preparing the polymorphsdescribed herein (including any one or more of polymorphic Forms I toXIII) may yield quantity and quality differences compared to the methodsfor preparing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneproduced on laboratory scale.

Form I

In one embodiment, provided is a method of producing a compositioncomprising polymorphic Form I of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the method comprises combining(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith hydrochloric acid and a solvent to produce a composition comprisingpolymorphic Form I of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the solvent is selected from the group consisting of methanol,ethanol, water, isopropyl acetate, ethyl acetate, methyl tert-butylether, n-heptane, acetonitrile, and any mixtures thereof.

In another embodiment, provided is a method of producing a compositioncomprising polymorphic Form I of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the method comprises combining a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith a solvent to produce a composition comprising polymorphic Form I ofthe hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the solvent is selected from the group consisting of methanol,ethanol, water, isopropyl acetate, ethyl acetate, methyl tert-butylether, n-heptane, acetonitrile, and any mixtures thereof.

Provided is a polymorphic Form I of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneproduced by combining(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith hydrochloric acid and a solvent, wherein the solvent is selectedfrom the group consisting of methanol, ethanol, water, isopropylacetate, ethyl acetate, methyl tert-butyl ether, n-heptane,acetonitrile, and any mixtures thereof.

Provided is also a polymorphic Form I of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneproduced by combining a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith a solvent, wherein the solvent is selected from the groupconsisting of methanol, ethanol, water, isopropyl acetate, ethylacetate, methyl tert-butyl ether, n-heptane, acetonitrile, and anymixtures thereof.

In certain embodiments of the polymorphic Form I produced according tothe methods described above, the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis a monohydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

Forms II and X

In one embodiment, provided is a method of producing a compositioncomprising polymorphic Form II, Form X, or a mixture thereof, of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the method comprises combining(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith hydrochloric acid and a solvent to produce a composition comprisingpolymorphic Form II, Form X, or a mixture thereof, of the hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the solvent is acetone.

In another embodiment, provided is a method of producing a compositioncomprising polymorphic Form II, Form X, or a mixture thereof, of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the method comprises combining a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith a solvent to produce a composition comprising polymorphic Form II,Form X, or a mixture thereof, of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the solvent is acetone.

Provided is a polymorphic Form II, Form X, or a mixture thereof, of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneproduced by combining(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith hydrochloric acid and a solvent, wherein the solvent is acetone.

Provided is also a polymorphic Form II, Form X, or a mixture thereof; ofa hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneprepared by combining a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith a solvent, wherein the solvent is acetone.

In certain embodiments of the polymorphic Form II, Form X, or a mixturethereof produced according to the methods described above, thehydrochloride saltof(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis a monohydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

Forms I and V

In one embodiment, provided is a method of producing a compositioncomprising polymorphic Form III, Form V, or a mixture thereof, of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the method comprises combining(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith hydrochloric acid and a solvent to produce a composition comprisingpolymorphic Form III, Form V, or a mixture thereof, of the hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the solvent is 2-methyltetrahydrofuran.

In another embodiment, provided is a method of producing a compositioncomprising polymorphic Form III, Form V, or a mixture thereof, of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the method comprises combining a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith a solvent to produce a composition comprising polymorphic Form III,Form V, or a mixture thereof; of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the solvent is 2-methyltetrahydrofuran.

Provided is a polymorphic Form III, Form V, or a mixture thereof; of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneproduced by combining(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith hydrochloric acid and a solvent, wherein the solvent is2-methyltetrahydrofuran.

Provided is also a polymorphic Form III, Form V, or a mixture thereof,of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneproduced by combining a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith a solvent, wherein the solvent is 2-methyltetrahydrofuran.

In certain embodiments of the polymorphic Form III, Form V, or a mixturethereof, produced according to the methods described above, thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis a monohydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

Forms IV and IX

In one embodiment, provided is a method of producing a compositioncomprising polymorphic Form IV, Form IX, or a mixture thereof, of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the method comprises combining(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith hydrochloric acid and a solvent to produce a composition comprisingpolymorphic Form IV, Form IX, or a mixture thereof of the hydrochloridesalt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the solvent is tetrahydrofuran.

In another embodiment, provided is a method of producing a compositioncomprising polymorphic Form IV, Form IX, or a mixture thereof, of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the method comprises combining a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith a solvent to produce a composition comprising polymorphic Form IV,Form IX, or a mixture thereof, of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the solvent is tetrahydrofuran.

Provided is a polymorphic Form IV, Form IX, or a mixture thereof, of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneproduced by combining(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith hydrochloric acid and a solvent, wherein the solvent istetrahydrofuran.

Provided is a polymorphic Form IV, Form IX, or a mixture thereof, of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneproduced by combining a hydrochloride saltof(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith a solvent, wherein the solvent is tetrahydrofuran.

In certain embodiments of the polymorphic Form IV, Form IX, or a mixturethereof; produced according to the methods described above, thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis a monohydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

Form VI

In one embodiment, provided is a method of producing a compositioncomprising polymorphic Form VI of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the method comprises combining(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith hydrochloric acid and a solvent to produce a composition comprisingpolymorphic Form VI of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the solvent is methyl isobutyl ketone.

In another embodiment, provided is a method of producing a compositioncomprising polymorphic Form VI of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the method comprises combining a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith a solvent to produce a composition comprising polymorphic Form VIof the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the solvent is methyl isobutyl ketone.

Provided is a polymorphic Form VI of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneproduced by combining(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith hydrochloric acid and a solvent, wherein the solvent is methylisobutyl ketone.

Provided is also a polymorphic Form VI of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneto produce a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith a solvent, wherein the solvent is methyl isobutyl ketone.

In certain embodiments of the polymorphic Form VI produced according tothe methods described above, the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis a monohydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

Form VII

In one embodiment, provided is a method of producing a compositioncomprising polymorphic Form VII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the method comprises combining(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith hydrochloric acid and a solvent to produce a composition comprisingpolymorphic Form VII of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the solvent is methyl ethyl ketone.

In another embodiment, provided is a method of producing a compositioncomprising polymorphic Form VII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the method comprises combining a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith a solvent to produce a composition comprising polymorphic Form VIIof the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the solvent is methyl ethyl ketone.

Provided is a polymorphic Form VII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneproduced by combining(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith hydrochloric acid and a solvent, wherein the solvent is methylethyl ketone.

Provided is also a polymorphic Form VII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneproduced by combining a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith a solvent, wherein the solvent is methyl ethyl ketone.

In certain embodiments of the polymorphic Form VII produced according tothe methods described above, the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis a monohydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

Form VIII

In one embodiment, provided is a method of producing a compositioncomprising polymorphic Form VIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the method comprises combining(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith hydrochloric acid and a solvent to produce a composition comprisingpolymorphic Form VIII of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the solvent is dichloromethane.

In another embodiment, provided is a method of producing a compositioncomprising polymorphic Form VIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the method comprises combining a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith a solvent to produce a composition comprising polymorphic Form VIIIof the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the solvent is dichloromethane.

Provided is a polymorphic Form VIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneproduced by combining(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith hydrochloric acid and a solvent, wherein the solvent isdichloromethane.

Provided is also a polymorphic Form VIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneprepared by combining a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith a solvent, wherein the solvent is dichloromethane.

In certain embodiments of the polymorphic Form VIII produced accordingto the methods described above, the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis a monohydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

Form XI

In one embodiment, provided is a method of producing a compositioncomprising polymorphic Form XI of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the method comprises combining(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith hydrochloric acid and a solvent to produce a composition comprisingpolymorphic Form XI of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the solvent is 2-propanol.

In another embodiment, provided is a method of producing a compositioncomprising polymorphic Form XI of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the method comprises combining a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith a solvent to produce a composition comprising polymorphic Form XIof the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the solvent is 2-propanol.

Provided is a polymorphic Form XI of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneproduced by combining(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith hydrochloric acid and a solvent, wherein the solvent is 2-propanol.

Provided is also a polymorphic Form XI of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneproduced by combining a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith a solvent, wherein the solvent is 2-propanol.

In certain embodiments of the polymorphic Form XI produced according tothe methods described above, the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis a monohydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

Form XII

In one embodiment, provided is a method of producing a compositioncomprising polymorphic Form XII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the method comprises combining(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith hydrochloric acid and a solvent to produce a composition comprisingpolymorphic Form XII of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the solvent is 1-propanol.

In another embodiment, provided is a method of producing a compositioncomprising polymorphic Form XII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the method comprises combining a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith a solvent to produce a composition comprising polymorphic Form XIIof the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the solvent is 1-propanol.

Provided is a polymorphic Form XII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneproduced by combining(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith hydrochloric acid and a solvent, wherein the solvent is 1-propanol.

Provided is also a polymorphic Form XII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneproduced by combining a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith a solvent, wherein the solvent is 1-propanol.

In certain embodiments of the polymorphic Form XII produced according tothe methods described above, the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis a monohydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

Form XIII

In one embodiment, provided is a method of producing a compositioncomprising polymorphic Form XIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the method comprises combining(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith hydrochloric acid and a solvent to produce a composition comprisingpolymorphic Form XIII of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the solvent is 1-butanol.

In another embodiment, provided is a method of producing a compositioncomprising polymorphic Form XIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the method comprises combining a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith a solvent to produce a composition comprising polymorphic Form XIIIof the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,wherein the solvent is 1-butanol.

Provided is a polymorphic Form XIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneproduced by combining(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith hydrochloric acid and a solvent, wherein the solvent is 1-butanol.

Provided is also a polymorphic Form XIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneproduced by combining a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith a solvent, wherein the solvent is 1-butanol.

In certain embodiments of the polymorphic Form XIII produced accordingto the methods described above, the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis a monohydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

The combination of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewith one or more suitable solvents, as described above, yields acomposition or mixture comprising the solvent and the one or morepolymorphic forms produced. In some instances where only a portion ofthe hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis converted into one or more polymorphic forms, the composition furthercomprises the hydrochloride salt. In some embodiments of the methodsdescribed above to produce the one or more polymorphic forms, the methodfurther comprises isolating the one or more polymorphic forms from theresulting composition. Any suitable techniques or methods known in theart to isolate the one or more polymorphic forms from the compositionmay be employed. For example, the solvent or mixture of solvents used inthe methods described above may be removed by known methods, such asfiltration and/or evaporation, to isolate the one or more polymorphicforms produced from the composition.

Pharmaceutical Compositions

The polymorphic forms described herein can be administered as the neatchemical, but it is typical, and preferable, to administer the compoundin the form of a pharmaceutical composition or formulation. Accordingly,provided are pharmaceutical compositions comprising one or more of thepolymorphic forms described herein (e.g., one or more of polymorphicForms I to XIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and any combinations thereof) and one or more pharmaceuticallyacceptable carriers, excipients, or other ingredients (including inertsolid diluents and fillers, diluents, including sterile aqueous solutionand various organic solvents, permeation enhancers, solubilizers andadjuvants). In certain embodiments, pharmaceutical compositionscomprising one or more of the polymorphic forms described herein (e.g.,one or more of polymorphic Forms I to XIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one)and one or more pharmaceutically acceptable excipients is provided. Incertain embodiments, pharmaceutical compositions comprising one or moreof the polymorphic forms described herein (e.g., one or more ofpolymorphic Forms I to XIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one)also include one or more additional therapeutic agents, as well as oneor more pharmaceutically acceptable excipients. The composition caninclude the polymorphic forms described herein either as the sole activeagent or in combination with other agents, such as oligo- orpolynucleotides, oligo- or polypeptides, drugs, or hormones mixed withone or more pharmaceutically acceptable carriers, excipients, or otheringredients. Carriers, excipients, and other ingredients can be deemedpharmaceutically acceptable insofar as they are compatible with otheringredients of the formulation and not deleterious to the recipientthereof.

Provided herein is a pharmaceutical composition comprising one or morepolymorphic forms of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onedescribed herein (e.g., one or more of polymorphic Forms I to XIII), anda pharmaceutical acceptable carrier or excipient.

Also provided herein is a pharmaceutical composition comprising one ormore polymorphic forms of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onedescribed herein (e.g., one or more of polymorphic Forms I to XIII), anda pharmaceutical acceptable excipient.

In one embodiment, the pharmaceutical composition comprises polymorphicForm I of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable carrier or excipient. In a furtherembodiment, the pharmaceutical composition comprises polymorphic Form Iof a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable excipient.

In another embodiment, the pharmaceutical composition comprisespolymorphic Form II of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable carrier or excipient. In anotherembodiment, the pharmaceutical composition comprises polymorphic Form IIof a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable excipient.

In another embodiment, the pharmaceutical composition comprisespolymorphic Form II of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable carrier or excipient. In anotherembodiment, the pharmaceutical composition comprises polymorphic FormIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable excipient.

In another embodiment, the pharmaceutical composition comprisespolymorphic Form IV of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable carrier or excipient. In anotherembodiment, the pharmaceutical composition comprises polymorphic Form IVof a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable excipient.

In yet another embodiment, the pharmaceutical composition comprisespolymorphic Form V of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable carrier or excipient. In yet anotherembodiment, the pharmaceutical composition comprises polymorphic Form Vof a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable excipient.

In yet another embodiment, the pharmaceutical composition comprisespolymorphic Form VI of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable carrier or excipient. In yet anotherembodiment, the pharmaceutical composition comprises polymorphic Form VIof a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable excipient.

In yet another embodiment, the pharmaceutical composition comprisespolymorphic Form VII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable carrier or excipient. In yet anotherembodiment, the pharmaceutical composition comprises polymorphic FormVII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable excipient.

In yet another embodiment, the pharmaceutical composition comprisespolymorphic Form VIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable carrier or excipient. In yet anotherembodiment, the pharmaceutical composition comprises polymorphic FormVIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable excipient.

In yet another embodiment, the pharmaceutical composition comprisespolymorphic Form IX of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable carrier or excipient. In yet anotherembodiment, the pharmaceutical composition comprises polymorphic Form IXof a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable excipient.

In yet another embodiment, the pharmaceutical composition comprisespolymorphic Form X of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable carrier or excipient. In yet anotherembodiment, the pharmaceutical composition comprises polymorphic Form Xof a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable excipient.

In yet another embodiment, the pharmaceutical composition comprisespolymorphic Form XI of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable carrier or excipient. In yet anotherembodiment, the pharmaceutical composition comprises polymorphic Form XIof a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable excipient.

In yet another embodiment, the pharmaceutical composition comprisespolymorphic Form XII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable carrier or excipient. In yet anotherembodiment, the pharmaceutical composition comprises polymorphic FormXII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable excipient.

In yet another embodiment, the pharmaceutical composition comprisespolymorphic Form XIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable carrier or excipient. In yet anotherembodiment, the pharmaceutical composition comprises polymorphic FormXIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable excipient.

Techniques for formulation and administration of pharmaceuticalcompositions can be found in Remington's Pharmaceutical Sciences, 18thEd., Mack Publishing Co, Easton, Pa., 1990. The pharmaceuticalcompositions described herein can be manufactured using any conventionalmethod, e.g., mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping, melt-spinning,spray-drying, or lyophilizing processes. An optimal pharmaceuticalformulation can be determined by one of skill in the art depending onthe route of administration and the desired dosage. Such formulationscan influence the physical state, stability, rate of in vivo release,and rate of in vivo clearance of the administered agent. Depending onthe condition being treated, these pharmaceutical compositions can beformulated and administered systemically or locally.

The pharmaceutical compositions can be formulated to contain suitablepharmaceutically acceptable carriers, and optionally can compriseexcipients and auxiliaries that facilitate processing of the polymorphicforms described herein into preparations that can be usedpharmaceutically. The mode of administration generally determines thenature of the carrier. For example, formulations for parenteraladministration can include aqueous solutions of the active compounds inwater-soluble form. Carriers suitable for parenteral administration canbe selected from among saline, buffered saline, dextrose, water, andother physiologically compatible solutions. Preferred carriers forparenteral administration are physiologically compatible buffers such asHanks's solution, Ringer's solution, or physiologically buffered saline.For tissue or cellular administration, penetrants appropriate to theparticular barrier to be permeated are used in the formulation. Suchpenetrants are generally known in the art. For preparations includingproteins, the formulation can include stabilizing materials, such aspolyols (e.g., sucrose) and/or surfactants (e.g., nonionic surfactants),and the like.

Alternatively, formulations for parenteral use can include dispersionsor suspensions of polymorphic forms described herein prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils, such as sesame oil, and synthetic fattyacid esters, such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions can contain substances that increase theviscosity of the suspension, such as sodium carboxymethylcellulose,sorbitol, dextran, and mixtures thereof. Optionally, the suspension alsocan contain suitable stabilizers or agents that increase the solubilityof the compounds to allow for the preparation of highly concentratedsolutions. Aqueous polymers that provide pH-sensitive solubilizationand/or sustained release of the active agent also can be used ascoatings or matrix structures, e.g., methacrylic polymers, such as theEUDRAGIT™ series available from Rohm America Inc. (Piscataway, N.J.).Emulsions, e.g., oil-in-water and water-in-oil dispersions, also can beused, optionally stabilized by an emulsifying agent or dispersant(surface active materials; surfactants). Suspensions can containsuspending agents such as ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar, gum tragacanth,and mixtures thereof.

Liposomes containing the polymorphic forms described herein also can beemployed for parenteral administration. Liposomes generally are derivedfrom phospholipids or other lipid substances. The compositions inliposome form also can contain other ingredients, such as stabilizers,preservatives, excipients, and the like. Preferred lipids includephospholipids and phosphatidyl cholines (lecithins), both natural andsynthetic. Methods of forming liposomes are known in the art. See, e.g.,Prescott (Ed.), Methods in Cell Biology, Vol. XIV, p. 33, AcademicPress, New York (1976).

In some embodiments, the polymorph or composition thereof disclosedherein is formulated for oral administration using pharmaceuticallyacceptable carriers, excipients or other ingredients well known in theart. Preparations formulated for oral administration can be in the formof tablets, pills, capsules, cachets, dragees, lozenges, liquids, gels,syrups, slurries, elixirs, suspensions, or powders. To illustrate,pharmaceutical preparations for oral use can be obtained by combiningthe active compounds with a solid excipient, optionally grinding theresulting mixture, and processing the mixture of granules, after addingsuitable auxiliaries if desired, to obtain tablets or dragee cores. Oralformulations can employ liquid carriers similar in type to thosedescribed for parenteral use, e.g., buffered aqueous solutions,suspensions, and the like.

In certain embodiments, the pharmaceutical compositions described hereinare in the form of tablets, pills or capsules. In a particularembodiment, the pharmaceutical compositions described herein are in theform of a tablet. Preferred oral formulations include tablets, dragees,and gelatin capsules. These preparations can contain one or moreexcipients, which include, without limitation:

-   -   a) diluents, such as microcrystalline cellulose and sugars,        including lactose, dextrose, sucrose, mannitol, or sorbitol;    -   b) binders, such as sodium starch glycolate, croscarmellose        sodium, magnesium aluminum silicate, starch from corn, wheat,        rice, potato, etc.;    -   c) cellulose materials, such as methylcellulose,        hydroxypropylmethyl cellulose, and sodium        carboxymethylcellulose, polyvinylpyrrolidone, gums, such as gum        arabic and gum tragacanth, and proteins, such as gelatin and        collagen;    -   d) disintegrating or solubilizing agents such as cross-linked        polyvinyl pyrrolidone, starches, agar, alginic acid or a salt        thereof, such as sodium alginate, or effervescent compositions;    -   e) lubricants, such as silica, talc, stearic acid or its        magnesium or calcium salt, and polyethylene glycol;    -   f) flavorants and sweeteners;    -   g) colorants or pigments, e.g., to identify the product or to        characterize the quantity (dosage) of active compound; and    -   h) other ingredients, such as preservatives, stabilizers,        swelling agents, emulsifying agents, solution promoters, salts        for regulating osmotic pressure, and buffers.

For example, provided is a tablet comprising one or more of thepolymorphic forms described herein (e.g., one or more of polymorphicForms I to XIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and any combinations thereof) and one or more pharmaceuticallyacceptable carriers or excipients. Also provided is a tablet comprisingone or more of the polymorphic forms described herein (e.g., one or moreof polymorphic Forms I to XIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and any combinations thereof) and one or more pharmaceuticallyacceptable excipients.

In one embodiment, the tablet comprises substantially pure polymorphicForm I of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and one or more pharmaceutically acceptable carriers or excipients. Inone embodiment, the tablet comprises substantially pure polymorphic FormI of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutically acceptable excipient.

In another embodiment, the tablet comprises substantially purepolymorphic Form II of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable carrier or excipient. In one embodiment,the tablet comprises substantially pure polymorphic Form II of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable excipient.

In another embodiment, the tablet comprises substantially purepolymorphic Form III of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable carrier or excipient. In one embodiment,the tablet comprises substantially pure polymorphic Form III of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable excipient.

In another embodiment, the tablet comprises substantially purepolymorphic Form IV of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable carrier or excipient. In one embodiment,the tablet comprises substantially pure polymorphic Form IV of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable excipient.

In yet another embodiment, the tablet comprises substantially purepolymorphic Form V of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable carrier or excipient. In one embodiment,the tablet comprises substantially pure polymorphic Form V of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable excipient.

In yet another embodiment, the tablet comprises substantially purepolymorphic Form VI of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable carrier or excipient. In one embodiment,the tablet comprises substantially pure polymorphic Form VI of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable excipient.

In yet another embodiment, the tablet comprises substantially purepolymorphic Form VII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable carrier or excipient. In one embodiment,the tablet comprises substantially pure polymorphic Form VII of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable excipient.

In yet another embodiment, the tablet comprises substantially purepolymorphic Form VIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable carrier or excipient. In one embodiment,the tablet comprises substantially pure polymorphic Form VIII of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable excipient.

In yet another embodiment, the tablet comprises substantially purepolymorphic Form IX of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable carrier or excipient. In one embodiment,the tablet comprises substantially pure polymorphic Form IX of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable excipient.

In yet another embodiment, the tablet comprises substantially purepolymorphic Form X of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable carrier or excipient. In one embodiment,the tablet comprises substantially pure polymorphic Form X of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable excipient.

In yet another embodiment, the tablet comprises substantially purepolymorphic Form XI of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable carrier or excipient. In one embodiment,the tablet comprises substantially pure polymorphic Form XI of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable excipient.

In yet another embodiment, the tablet comprises substantially purepolymorphic Form XII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable carrier or excipient. In one embodiment,the tablet comprises substantially pure polymorphic Form XII of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable excipient.

In yet another embodiment, the tablet comprises substantially purepolymorphic Form XIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable carrier or excipient. In one embodiment,the tablet comprises substantially pure polymorphic Form XIII of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a pharmaceutical acceptable excipient.

In any of the foregoing tablets, in one variation, the tablet issubstantially free of amorphous or non-crystalline hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In another embodiment, in any of the foregoing tablets, the tablet isfree of amorphous or non-crystalline hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

Gelatin capsules include push-fit capsules made of gelatin, as well assoft, sealed capsules made of gelatin and a coating such as glycerol orsorbitol. Push-fit capsules can contain the active ingredient(s) mixedwith fillers, binders, lubricants, and/or stabilizers, etc. In softcapsules, the active compounds can be dissolved or suspended in suitablefluids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycol with or without stabilizers.

Dragee cores can be provided with suitable coatings such as concentratedsugar solutions, which also can contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide,lacquer solutions, and suitable organic solvents or solvent mixtures.

The compositions are preferably formulated in a unit dosage form. Theterm “unit dosage forms” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical excipient (e.g., a tablet, capsule, ampoule). Thepolymorphs described herein are effective over a wide dosage range andare generally administered in a pharmaceutically effective amount. Itwill be understood, however, that the amount of the polymorph actuallyadministered will be determined by a physician, in the light of therelevant circumstances, including the condition to be treated, thechosen route of administration, the age, weight, and response of thesubject receiving such treatment, the severity of the subject'ssymptoms, and the like.

The tablets or pills described herein may be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction, or to protect from the acid conditions of the stomach. Forexample, the tablet or pill can comprise an inner dosage and an outerdosage element, the latter being in the form of an envelope over theformer. The two elements can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innerelement to pass intact into the duodenum or to be delayed in release. Avariety of materials can be used for such enteric layers or coatings,such materials including a number of polymorphic acids and mixtures ofpolymorphic acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

For example, provided is a unit dosage comprising one or more of thepolymorphic forms described herein (e.g., one or more of polymorphicForms I to XIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In one embodiment, the unit dosage comprises polymorphic Form I of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In another embodiment, the unit dosage comprises polymorphic Form II ofa hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In another embodiment, the unit dosage comprises polymorphic Form III ofa hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In another embodiment, the unit dosage comprises polymorphic Form IV ofa hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In yet another embodiment, the unit dosage comprises polymorphic Form Vof a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In yet another embodiment, the unit dosage comprises polymorphic Form VIof a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In yet another embodiment, the unit dosage comprises polymorphic FormVII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In yet another embodiment, the unit dosage comprises polymorphic FormVIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In yet another embodiment, the unit dosage comprises polymorphic Form IXof a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In yet another embodiment, the unit dosage comprises polymorphic Form Xof a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In yet another embodiment, the unit dosage comprises polymorphic Form XIof a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In yet another embodiment, the unit dosage comprises polymorphic FormXII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In yet another embodiment, the unit dosage comprises polymorphic FormXIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In any of the foregoing unit dosage forms, in certain embodiments, thehydrochloride salt is a monohydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In any of the foregoing unit dosage forms, in one variation, the unitdosage form is substantially free of amorphous or non-crystallinehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

In certain embodiments, in any of the foregoing unit dosage forms, thetablet further includes one or more excipients.

In certain embodiments, the unit dosage forms described herein include75-300 mg of the polymorphic forms described herein. In certainembodiments, the unit dosage forms described herein include 75-200 mg ofthe polymorphic forms described herein. In certain embodiments, the unitdosage forms described herein include 75-150 mg of the polymorphic formsdescribed herein. In certain embodiments, the unit dosage formsdescribed herein include 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg,250 mg, or 300 mg of the polymorphic forms described herein. In certainembodiments, the unit dosage forms described herein include 75 mg, 100mg, 150 mg, or 200 mg of the polymorphic forms described herein. Incertain embodiments, the unit dosage forms described herein include 100mg or 150 mg 200 mg of the polymorphic forms described herein.

Modes of Administration and Dosages

Pharmaceutical compositions including the polymorphic forms describedherein can be administered to the subject by any conventional method,including parenteral and enteral techniques. Parenteral administrationmodalities include those in which the composition is administered by aroute other than through the gastrointestinal tract, for example,intravenous, intraarterial, intraperitoneal, intramedullary,intramuscular, intraarticular, intrathecal, and intraventricularinjections. Enteral administration modalities include, for example,oral, buccal, sublingual, and rectal administration. Transepithelialadministration modalities include, for example, transmucosaladministration and transdermal administration. Transmucosaladministration includes, for example, enteral administration as well asnasal, inhalation, and deep lung administration; vaginal administration;and buccal and sublingual administration. Transdermal administrationincludes passive or active transdermal or transcutaneous modalities,including, for example, patches and iontophoresis devices, as well astopical application of pastes, salves, or ointments. Parenteraladministration also can be accomplished using a high-pressure technique,e.g., POWDERJECT™.

Moreover, the therapeutic index of the compound having the polymorphicforms described herein can be enhanced by modifying or derivatizing thecompound for targeted delivery to cancer cells expressing a marker thatidentifies the cells as such. For example, the compound can be linked toan antibody that recognizes a marker that is selective or specific forcancer cells, so that the compounds are brought into the vicinity of thecells to exert their effects locally, as previously described. See e.g.,Pietersz et al., Immunol. Rev., 129:57 (1992); Trail et al., Science,261:212 (1993); and Rowlinson-Busza et al., Curr. Opin. Oncol., 4:1142(1992). Tumor-directed delivery of the compound can enhance thetherapeutic benefit by, inter alia, minimizing potential nonspecifictoxicities that can result from radiation treatment or chemotherapy. Insome embodiments, the compound having a polymorphic form describedherein, and radioisotopes or chemotherapeutic agents can be conjugatedto the same anti-tumor antibody.

Pharmacokinetic and pharmacodynamic information about the polymorphicforms described herein and the formulation of the compound having apolymorphic form described herein can be collected through preclinicalin vitro and in vivo studies, later confirmed in humans during thecourse of clinical trials. Thus, for the compound having a polymorphicform described herein used in the methods described herein, atherapeutically effective dose can be estimated initially frombiochemical and/or cell-based assays. Then, dosage can be formulated inanimal models to achieve a desirable circulating concentration rangethat modulates PI3Kδ expression or activity. As human studies areconducted further information will emerge regarding the appropriatedosage levels and duration of treatment for various diseases andconditions.

Toxicity and therapeutic efficacy of such compounds can be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., for determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe “therapeutic index”, which typically is expressed as the ratioLD₅₀/ED₅₀. Compounds that exhibit large therapeutic indices, i.e., thetoxic dose is substantially higher than the effective dose, arepreferred. The data obtained from such cell culture assays andadditional animal studies can be used in formulating a range of dosagefor human use. The dosage of such compounds lies preferably within arange of circulating concentrations that include the ED.sub.50 withlittle or no toxicity.

It should be understood that any effective administration regimenregulating the timing and sequence of doses can be used. A compoundhaving a polymorphic form described herein and pharmaceuticalcompositions thereof may include those wherein the active ingredient isadministered in an effective amount to achieve its intended purpose.

In some embodiments, a “therapeutically effective amount” means anamount sufficient to modulate PI3K expression or activity, includingPI3Kδ expression or activity, and thereby treat a subject (e.g., ahuman) suffering an indication, or to alleviate the existing symptoms ofthe indication.

Exemplary dosage levels for a human subject may be of the order of fromabout 0.001 milligram of active agent per kilogram body weight (mg/kg)to about 1000 mg/kg. Dosage units of the active agent may comprise fromabout 0.01 mg to about 1000 mg, or from about 0.1 mg to about 100 mg,depending upon the indication, route of administration, and severity ofthe condition, for example. Depending on the route of administration, asuitable dose can be calculated according to body weight, body surfacearea, or organ size. For example, when administered orally, the totaldaily dosage for a human subject may be between 1 mg and 1,000 mg,between about 10-500 mg/day, between about 50-300 mg/day, between about75-200 mg/day, or between about 100-150 mg/day. In certain embodiments,the total daily dosage for a human subject is about 150-300 mg/day. Incertain embodiments, the total daily dosage for a human subject is about200-300 mg/day. In certain embodiments, the total daily dosage for ahuman subject is 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg,or 300 mg. In certain embodiments, the total daily dosage for a humansubject is 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg. In certainembodiments, the total daily dosage for a human subject is 150 mg, 200mg, or 300 mg. In certain embodiments, the total daily dosage for ahuman subject is 200 mg or 300 mg. In certain embodiments, the totaldaily dosage for a human subject is 100 mg or 150 mg. The final dosageregimen is determined by the attending physician in view of good medicalpractice, considering various factors that modify the action of drugs,e.g., the specific activity of the compound, the identity and severityof the disease state, the responsiveness of the subject, the age,condition, body weight, sex, and diet of the subject, and the severityof any infection. Additional factors that can be taken into accountinclude time and frequency of administration, drug combinations,reaction sensitivities, and tolerance/response to therapy. Furtherrefinement of the dosage appropriate for treatment involving any of theformulations mentioned herein is done routinely by the skilledpractitioner without undue experimentation, especially in light of thedosage information and assays disclosed, as well as the pharmacokineticdata observed in human clinical trials. Appropriate dosages can beascertained through use of established assays for determiningconcentration of the agent in a body fluid or other sample together withdose response data.

The frequency of dosing depends on the pharmacokinetic parameters of theagent and the route of administration. Dosage and administration areadjusted to provide sufficient levels of the active moiety or tomaintain the desired effect. Accordingly, the pharmaceuticalcompositions can be administered in a single dose, multiple discretedoses, continuous infusion, sustained release depots, or combinationsthereof; as required to maintain desired minimum level of the agent.Short-acting pharmaceutical compositions (i.e., short half-life) can beadministered once a day or more than once a day (e.g., two, three, orfour times a day). Long acting pharmaceutical compositions might beadministered every 3 to 4 days, every week, or once every two weeks.

In certain embodiments, the pharmaceutical composition disclosed hereinare administered once, twice, or three times daily. In certainembodiments, the pharmaceutical composition disclosed herein areadministered once or twice daily. In certain embodiments, thepharmaceutical composition disclosed herein are administered once daily.

Bioequivalents of the Polymorphs

Also provided herein are polymorphs that are bioequivalent to any one ormore of polymorphic Forms I to XIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onedescribed herein.

In certain embodiments, bioequivalence between two polymorphs refers topolymorphs having substantially similar bioavailability, substantiallysimilar efficacy, substantially similar safety profiles, or acombination thereof.

In yet other embodiments, bioequivalence refers to polymorphs thatexhibit substantially similar pharmacokinetic profiles or therapeuticeffects. Bioequivalence may be demonstrated through several in vivo andin vitro methods. These methods may include, for example,pharmacokinetic, pharmacodynamic, clinical and in vitro studies. In someembodiments, bioequivalence can be demonstrated using any suitablepharmacokinetic measures or combination of pharmacokinetic measuresknown in the art, including loading dose, steady-state dose, initial orsteady-state concentration of drug, biological half-life, eliminationrate, area under the curve (AUC), clearance, the peak blood or plasmaconcentration (C_(max)), time to peak concentration (T_(max)),bioavailability and potency. In some embodiments, bioequivalence isachieved with similar dosing amounts. In alternative embodiments,bioequivalence is achieved with different dosing amounts.

Uses of the Polymorphs and Compositions Thereof

Therapeutic Uses

Provided are also a use of the polymorphs or compositions thereofdescribed herein to selectively or specifically inhibit PI3Kδ activitytherapeutically or prophylactically. The method comprises administeringthe polymorphs or compositions thereof to a subject (e.g., a human) inneed thereof in an amount sufficient to inhibit PI3Kδ activity. Themethod can be employed to treat humans or animals suffering from, orsubject to, a condition whose symptoms or pathology is mediated by PI3Kδexpression or activity.

“Treatment” or “treating” is an approach for obtaining beneficial ordesired results including clinical results. Beneficial or desiredclinical results may include one or more of the following:

-   -   (i) decreasing one more symptoms resulting from the disease;    -   (ii) diminishing the extent of the disease and/or stabilizing        the disease (e.g., delaying the worsening of the disease);    -   (iii) delaying the spread (e.g., metastasis) of the disease;    -   (iv) delaying or slowing the recurrence of the disease and/or        the progression of the disease;    -   (v) ameliorating the disease state and/or providing a remission        (whether partial or total) of the disease and/or decreasing the        dose of one or more other medications required to treat the        disease;

(vi) increasing the quality of life; and/or

-   -   (vii) prolonging survival.

In some embodiments, “disorder” is intended to encompass medicaldisorders, diseases, conditions, syndromes, and the like, withoutlimitation.

The methods disclosed in the application embrace various modes oftreating an animal subject, preferably a mammal, more preferably aprimate, and still more preferably a human. Among the mammalian animalsthat can be treated are, for example, humans; companion animals (pets),including dogs and cats; farm animals, including cattle, horses, sheep,pigs, and goats; laboratory animals, including rats, mice, rabbits,guinea pigs, and nonhuman primates; and zoo specimens. Among thenon-mammalian animals that can be treated include, for example, birds,fish, reptiles, and amphibians.

In one aspect, the polymorphs and compositions thereof described hereincan be employed in methods of inhibiting the growth or proliferation ofcancer cells of hematopoietic origin, such as cancer cells. In someembodiments, the cancer cells are of lymphoid origin, and in specificembodiments, the cancer cells are related to or derived from Blymphocytes or B lymphocyte progenitors. In another aspect, thepolymorphs and compositions thereof described herein can be employed inmethods of treating a human with a cancer.

Cancers amenable to treatment using the method disclosed in theapplication include, for example, lymphomas (e.g., malignant neoplasmsof lymphoid and reticuloendothelial tissues, such as Burkitt's lymphoma,Hodgkins' lymphoma, non-Hodgkins' lymphomas, lymphocytic lymphomas);multiple myelomas; leukemias (e.g., lymphocytic leukemias, chronicmyeloid (myelogenous) leukemias), and solid tumor (e.g., pancreatic).Other cancer cells, of hematopoietic origin or otherwise, that expressp110δ also can be treated by administration of the polymorphs andcompositions thereof described herein.

In other embodiments, the forms described herein may be used to treatcancers that are mediated by, dependent on or associated with PI3Kactivity, such as PI3Kδ activity. In certain embodiments, the cancer isa hematologic malignancy. In certain embodiments, the cancer islymphoma, multiple myeloma, or leukemia. In certain embodiments, thecancer is a solid tumor cancer. In particular embodiments, thehematologic malignancy is leukemia or lymphoma. In specific embodiments,the cancer is acute lymphocytic leukemia (ALL), acute myeloid leukemia(AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma(SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD),chronic myeloid leukemia (CML), juvenile myelomonocytic leukemia (JMML),multiple myeloma (MM), Hodgkin lymphoma, non-Hodgkin's lymphoma (NHL),indolent non-Hodgkin's lymphoma (iNHL), refractory iNHL, mantle celllymphoma (MCL), follicular lymphoma, Waldestrom's macroglobulinemia(WM), minimal residual disease (MRD), T-cell lymphoma, B-cell lymphoma,diffuse large B-cell lymphoma (DLBCL), T-cell acute lymphoblasticleukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL),lymphoplasmacytic lymphoma, marginal zone lymphoma, Burkitt lymphoma, orfollicular B-cell non-Hodgkin lymphoma (FL). In one embodiment, thecancer is T-cell acute lymphoblastic leukemia (T-ALL), or B-cell acutelymphoblastic leukemia (B-ALL). In one embodiment, the cancer isindolent non-Hodgkin's lymphoma (iNHL). It should be understood thatnon-Hodgkin's lymphoma may, in certain embodiments, encompass theindolent B-cell diseases that include, for example, follicular lymphoma,lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, and marginalzone lymphoma, as well as the aggressive lymphomas that include, forexample, Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL) andmantle cell lymphoma (MCL). In certain embodiments, the forms describedherein may be used to treat chronic lymphocytic leukemia (CLL),follicular B-cell non-Hodgkin lymphoma (FL), or small lymphocyticlymphoma (SLL). In certain embodiments, the forms described herein maybe used to treat relapsed chronic lymphocytic leukemia (CLL), relapsedfollicular B-cell non-Hodgkin lymphoma (FL), or relapsed smalllymphocytic lymphoma (SLL). In certain embodiments, the forms describedherein may be used to treat non-Hodgkin's lymphoma (NHL) or indolentnon-Hodgkin's lymphoma (iNHL). In certain embodiments, the formsdescribed herein may be used to treat relapsed non-Hodgkin's lymphoma(NHL) or relapsed indolent non-Hodgkin's lymphoma (iNHL).

In another aspect, the polymorphs and compositions thereof describedherein can be employed in methods of treating an autoimmune disease. Insome embodiments, the autoimmune disease is systemic lupus erythematosus(SLE), myestenia gravis, rheumatoid arthritis (RA), acute disseminatedencephalomyelitis, idiopathic thrombocytopenic purpura, multiplesclerosis (MS), Sjoegren's syndrome, psoriasis, autoimmune hemolyticanemia, asthma, or chronic obstructive pulmonary disease (COPD). Inparticular embodiments, the autoimmune disease is asthma, rheumatoidarthritis, multiple sclerosis, or lupus.

In yet another aspect, provided are methods of treating a human having aPI3K-mediated disorder by administering one or more of the polymorphicforms described herein (e.g., one or more of polymorphic Forms I, II,III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII) to the human. Inanother aspect, provided are methods of treating a human having aPI3K-mediated disorder by administering one or more of the polymorphicforms described herein (e.g., one or more of the solvate formscorresponding to Pattern 1, 2, 3, 4, or the 2-methyl-1-propanol solvate,or the 1,4-dioxane solvate, or the toluene solvate) to the human.Provided are also methods of modulating PI3K an individual byadministering one or more of the polymorphic forms described herein(e.g., one or more of polymorphic Forms I to XIII a hydrochloride saltof(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.In one variation, the human has cancer, such as leukemia or lymphoma. Inanother variation, the human has an autoimmune disease, such as asthma,rheumatoid arthritis, multiple sclerosis, or lupus.

In any of the foregoing methods, one or more polymorphic forms may beadministered to the individual as unit dosage, for example in the formof a tablet, as described herein. Exemplary unit dosage levels ofpolymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII andXIII, for a human subject may, in certain variations, be between about0.01 mg to about 1000 mg, between about 1 mg to about 15 mg, or betweenabout 50 mg to about 200 mg, or about 5 mg, about 10 mg, about 15 mg,about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, orabout 150 mg, or about 175 mg, about 200 mg, or about 250 mg.

In another aspect, polymorphic forms described herein (e.g., polymorphicForms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII) may beused in combination with one or more additional therapeutic agent thatare being used and/or developed to treat cancers or inflammatorydisorders. The one or more additional therapeutic agent may be aninhibitor to PI3K such as PI3Kγ, PI3Kβ, and/or PI3Kα, Janus kinase (JAK)such as JAK1, JAK2 and/or JAK3, spleen tyrosine kinase (SYK), Bruton'styrosine kinase (BTK), bromodomain containing protein inhibitor (BRD)such as BRD4, a lysyl oxidase protein (LOX), lysyl oxidase-like protein(LOXL) such as LOXL1-5, matrix metalloprotease (MMP) such as MMP 1-10,adenosine A2B receptor (A2B), isocitrate dehydrogenase (IDH) such asIDH1, apoptosis signal-regulating kinase (ASK) such as ASK1,serine/threonine kinase TPL2, discoidin domain receptor (DDR) such asDDR1 and DDR2, histone deacetylase (HDAC), protein kinase C (PKC), ormonoclonal antibody (such as an anti-CD20 monoclonal antibody or ananti-CD39 monoclonal antibody) or any combination thereof.

One, two, three, or more of the therapeutic agents (e.g. a PI3Kinhibitor, a JAK inhibitor, a SYK inhibitor, a BTK inhibitor, a BRD4inhibitor, a LOXL2 inhibitor, a MMP9 inhibitor, a A2B inhibitor, an IDHinhibitor, an ASK inhibitor, a TPL2 inhibitor, a DDR1 inhibitor, a TBKinhibitor, a HDAC inhibitor, a PKC inhibitor, or a monoclonal antibody)may be further used or combined with a chemotherapeutic agent, animmunotherapeutic agent, a radiotherapeutic agent, an anti-neoplasticagent, an anti-cancer agent, an anti-fibrotic agent, an anti-angiogenicagent, a therapeutic antibody, or any combination thereof.

Chemotherapeutic agents may be categorized by their mechanism of actioninto, for example, the following groups: anti-metabolites/anti-canceragents, such as pyrimidine analogs (floxuridine, capecitabine, andcytarabine); purine analogs, folate antagonists and related inhibitorsantiproliferative/antimitotic agents including natural products such asvinca alkaloid (vinblastine, vincristine) and microtubule such as taxane(paclitaxel, docetaxel), vinblastin, nocodazole, epothilones andnavelbine, epidipodophyllotoxins (etoposide, teniposide); DNA damagingagents (actinomycin, amsacrine, busulfan, carboplatin, chlorambucil,cisplatin, cyclophosphamide, Cytoxan, dactinomycin, daunorubicin,doxorubicin, epirubicin, iphosphamide, melphalan, merchlorehtamine,mitomycin, mitoxantrone, nitrosourea, procarbazine, taxol, taxotere,teniposide, etoposide, triethylenethiophosphoramide); antibiotics suchas dactinomycin (actinomycin D), daunorubicin, doxorubicin (adriamycin),idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin(mithramycin) and mitomycin; enzymes (L-asparaginase which systemicallymetabolizes L-asparagine and deprives cells which do not have thecapacity to synthesize their own asparagine); antiplatelet agents;antiproliferative/antimitotic alkylating agents such as nitrogenmustards cyclophosphamide and analogs (bendamustine, melphalan,chlorambucil), and (hexamethylmelamine and thiotepa), alkyl nitrosoureas(BCNU) and analogs, streptozocin), trazenes-dacarbazinine (DTIC);antiproliferative/antimitotic antimetabolites such as folic acid analogs(methotrexate); platinum coordination complexes (cisplatin,oxiloplatinim, carboplatin), procarbazine, hydroxyurea, mitotane,aminoglutethimide; hormones, hormone analogs (estrogen, tamoxifen,goserelin, bicalutamide, nilutamide) and aromatase inhibitors(letrozole, anastrozole); anticoagulants (heparin, synthetic heparinsalts and other inhibitors of thrombin); fibrinolytic agents (such astissue plasminogen activator, streptokinase and urokinase), aspirin,dipyridamole, ticlopidine, clopidogrel; antimigratory agents;antisecretory agents (breveldin); immunosuppressives tacrolimussirolimus azathioprine, mycophenolate; compounds (TNP-470, genistein)and growth factor inhibitors (vascular endothelial growth factorinhibitors, fibroblast growth factor inhibitors); angiotensin receptorblocker, nitric oxide donors; anti-sense oligonucleotides; antibodies(trastuzumab, rituximab); cell cycle inhibitors and differentiationinducers (tretinoin); inhibitors, topoisomerase inhibitors (doxorubicin(adriamycin), daunorubicin, dactinomycin, eniposide, epirubicin,etoposide, idarubicin, irinotecan and mitoxantrone, topotecan,irinotecan, camptothesin), corticosteroids (cortisone, dexamethasone,hydrocortisone, methylpednisolone, prednisone, and prenisolone); growthfactor signal transduction kinase inhibitors; dysfunction inducers,toxins such as Cholera toxin, ricin, Pseudomonas exotoxin, Bordetellapertussis adenylate cyclase toxin, or diphtheria toxin, and caspaseactivators; and chromatin.

As used herein the term “chemotherapeutic agent” or “chemotherapeutic”(or “chemotherapy”, in the case of treatment with a chemotherapeuticagent) may encompass any non-proteinaceous (e.g., non-peptidic) chemicalcompound useful in the treatment of cancer. Examples of chemotherapeuticagents include alkylating agents such as bendamustine, thiotepa andcyclophosphamide (CYTOXAN™); alkyl sulfonates such as busulfan,improsulfan and piposulfan; aziridines such as benzodopa, carboquone,meturedopa, and uredopa; emylerumines and memylamelamines includingalfretamine, triemylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide and trimemylolomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (includingsynthetic analogue topotecan); bryostatin; callystatin; CC-1065(including its adozelesin, carzelesin and bizelesin syntheticanalogues); cryptophycins (articularly cryptophycin 1 and cryptophycin8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189and CBI-TMI); eleutherobin; pancratistatin; a sarcodictyin;spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine,cholophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureassuch as carmustine, chlorozotocin, foremustine, lomustine, nimustine,ranimustine; antibiotics such as the enediyne antibiotics (e.g.,calicheamicin, especially calicheamicin gammaII and calicheamicin phiI1,see, e.g., Agnew, Chem. Intl. Ed. Engl, 33:183-186 (1994); dynemicin,including dynemicin A; bisphosphonates, such as clodronate; anesperamicin; as well as neocarzinostatin chromophore and relatedchromoprotein enediyne antibiotic chromomophores), aclacinomysins,actinomycin, authramycin, azaserine, bleomycins, cactinomycin,carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin,daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin(including morpholino-doxorubicin, cyanomorpholino-doxorubicin,2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolicacid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubanimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogues such as demopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogues such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replinisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; hestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elformthine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine;maytansinoids such as maytansine and ansamitocins; mitoguazone;mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin;losoxantrone; fluoropyrimidine; folinic acid; podophyllinic acid;2-ethylhydrazide; procarbazine; PSK®; razoxane; rhizoxin; sizofiran;spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-tricUorotriemylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethane; vindesine;dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman;gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiopeta; taxoids,e.g., paclitaxel (TAXOL®, Bristol Meyers Squibb Oncology, Princeton,N.J.) and docetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France);chlorambucil; gemcitabine (Gemzar®); 6-thioguanine; mercaptopurine;methotrexate; platinum analogs such as cisplatin and carboplatin;vinblastine; platinum; etoposide (VP-16); ifosfamide; mitroxantrone;vancristine; vinorelbine (Navelbine®); novantrone; teniposide;edatrexate; daunomycin; aminopterin; xeoloda; ibandronate; CPT-1;topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO);retinoids such as retinoic acid; capecitabine; FOLFIRI (fluorouracil,leucovorin, and irinotecan) and pharmaceutically acceptable salts, acidsor derivatives of any of the above. One or more chemotherapeutic agentare used or included in the present application. For example,gemcitabine, nab-paclitaxel, and gemcitabine/nab-paclitaxel are usedwith the JAK inhibitor and/or PI3Kδ inhibitor for treatinghyperproliferative disorders.

Chemotherapeutic agents may also include, for example, anti-hormonalagents that act to regulate or inhibit hormone action on tumors such asanti-estrogens and selective estrogen receptor modulators (SERMs),including, for example, tamoxifen (including Nolvadex™), raloxifene,droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018,onapristone, and toremifene (Fareston®); inhibitors of the enzymearomatase, which regulates estrogen production in the adrenal glands,such as, for example, 4(5)-imidazoles, aminoglutethimide, megestrolacetate (Megace®), exemestane, formestane, fadrozole, vorozole(Rivisor®), letrozole (Femara®), and anastrozole (Arimidex®); andanti-androgens such as flutamide, nilutamide, bicalutamide, leuprohde,and goserelin; and pharmaceutically acceptable salts, acids orderivatives of any of the above.

The anti-angiogenic agents include, but are not limited to, retinoidacid and derivatives thereof; 2-methoxyestradiol, ANGIOSTATIN,ENDOSTATIN, suramin, squalamine, tissue inhibitor ofmetalloproteinase-1, tissue inhibitor of metalloproteinase-2,plasminogen activator inhibitor-1, plasminogen activator inhibitor-2,cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), plateletfactor 4, protamine sulphate (clupeine), sulphated chitin derivatives(prepared from queen crab shells), sulphated polysaccharidepeptidoglycan complex (sp-pg), staurosporine, modulators of matrixmetabolism, including for example, proline analogs((1-azetidine-2-carboxylic acid (LACA), cishydroxyproline,d,I-3,4-dehydroproline, thiaproline, .alpha.-dipyridyl,beta-aminopropionitrile fumarate,4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone; methotrexate, mitoxantrone,heparin, interferons, 2 macroglobulin-serum, chimp-3, chymostatin,beta-cyclodextrin tetradecasulfate, eponemycin; fumagillin, gold sodiumthiomalate, d-penicillamine (CDPT), beta-1-anticollagenase-serum,alpha-2-antiplasmin, bisantrene, lobenzarit disodium,n-2-carboxyphenyl-4-chloroanthronilic acid disodium or “CCA”,thalidomide; angiostatic steroid, cargboxynaminolmidazole;metalloproteinase inhibitors such as BB94. Other anti-angiogenesisagents include antibodies, preferably monoclonal antibodies againstthese angiogenic growth factors: beta-FGF, alpha-FGF, FGF-5, VEGFisoforms, VEGF-C, HGF/SF and Ang-1/Ang-2. See Ferrara N. and Alitalo, K.“Clinical application of angiogenic growth factors and their inhibitors”(1999) Nature Medicine 5:1359-1364.

The anti-fibrotic agents include, but are not limited to, the compoundssuch as beta-aminoproprionitrile (BAPN), as well as the compoundsdisclosed in U.S. Pat. No. 4,965,288 to Palfreyman, et al., issued Oct.23, 1990, entitled “Inhibitors of lysyl oxidase,” relating to inhibitorsof lysyl oxidase and their use in the treatment of diseases andconditions associated with the abnormal deposition of collagen; U.S.Pat. No. 4,997,854 to Kagan, et al., issued Mar. 5, 1991, entitled“Anti-fibrotic agents and methods for inhibiting the activity of lysyloxidase in situ using adjacently positioned diamine analogue substrate,”relating to compounds which inhibit LOX for the treatment of variouspathological fibrotic states, which are herein incorporated byreference. Further exemplary inhibitors are described in U.S. Pat. No.4,943,593 to Palfreyman, et al., issued Jul. 24, 1990, entitled“Inhibitors of lysyl oxidase,” relating to compounds such as2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine; as well as, e.g.,U.S. Pat. No. 5,021,456; U.S. Pat. No. 5,5059,714; U.S. Pat. No.5,120,764; U.S. Pat. No. 5,182,297; U.S. Pat. No. 5,252,608 (relating to2-(1-naphthyloxymemyl)-3-fluoroallylamine); and U.S. Patent ApplicationNo. 2004/0248871, which are herein incorporated by reference in theirentirety. Exemplary anti-fibrotic agents also include the primary aminesreacting with the carbonyl group of the active site of the lysyloxidases, and more particularly those which produce, after binding withthe carbonyl, a product stabilized by resonance, such as the followingprimary amines: emylenemamine, hydrazine, phenylhydrazine, and theirderivatives, semicarbazide, and urea derivatives, aminonitriles, such asbeta-aminopropionitrile (BAPN), or 2-nitroethylamine, unsaturated orsaturated haloamines, such as 2-bromo-ethylamine, 2-chloroethylamine,2-trifluoroethylamine, 3-bromopropylamine, p-halobenzylamines,selenohomocysteine lactone. Also, the anti-fibrotic agents are copperchelating agents, penetrating or not penetrating the cells. Exemplarycompounds include indirect inhibitors such compounds blocking thealdehyde derivatives originating from the oxidative deamination of thelysyl and hydroxylysyl residues by the lysyl oxidases, such as thethiolamines, in particular D-penicillamine, or its analogues such as2-amino-5-mercapto-5-methylhexanoic acid,D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid,p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid,sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulphurate,2-acetamidoethyl-2-acetamidoethanethiol sulphanate,sodium-4-mercaptobutanesulphinate trihydrate.

The immunotherapeutic agents include and are not limited to therapeuticantibodies suitable for treating patients; such as abagovomab,adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab,anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab,bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab,cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab,daratumumab, drozitumab, duligotumab, dusigitumab, detumomab,dacetuzumab, dalotuzumab, ecromeximab, elotuzumab, ensituximab,ertumaxomab, etaracizumab, farietuzumab, ficlatuzumab, figitumumab,flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab,glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab,inotuzumab, intetumumab, ipilimumab, iratumumab, labetuzumab,lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab,matuzumab, milatuzumab, minrctumomab, mitumomab, moxetumomab,narnatumab, naptumomab, necitumumab, nimotuzumab, nofetumomabn,ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab,oregovomab, panitumumab, parsatuzumab, patritumab, pemtumomab,pertuzumab, pintumomab, pritumumab, racotumomab, radretumab,rilotumumab, rituximab, robatumumab, satumomab, sibrotuzumab,siltuximab, simtuzumab, solitomab, tacatuzumab, taplitumomab,tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab,tucotuzumab, ublituximab, veltuzumab, vorsetuzumab, votumumab,zalutumumab, CC49 and 3F8. The exemplified therapeutic antibodies may befurther labeled or combined with a radioisotope particle, such as indiumIn 111, yttrium Y 90, iodine I-131.

The application also provides a method for treating a subject who isundergoing one or more standard therapies, such as chemotherapy,radiotherapy, immunotherapy, surgery, or combination thereof.Accordingly, one or more therapeutic agent or inhibitors may beadministered before, during, or after administration of chemotherapy,radiotherapy, immunotherapy, surgery or combination thereof.

In certain embodiments, the subject may be a human who is (i)substantially refractory to at least one chemotherapy treatment, or (ii)in relapse after treatment with chemotherapy, or both (i) and (ii). Insome of embodiments, the subject is refractory to at least two, at leastthree, or at least four chemotherapy treatments (including standard orexperimental chemotherapies).

In certain embodiments, the subject is refractory to at least one, atleast two, at least three, or at least four chemotherapy treatment(including standard or experimental chemotherapy) selected fromfludarabine, rituximab, obinutuzumab, alkylating agents, alemtuzumab andother chemotherapy treatments such as CHOP (cyclophosphamide,doxorubicin, vincristine, prednisone); R-CHOP (rituximab-CHOP);hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin,dexamethasone, methotrexate, cytarabine); R-hyperCVAD(rituximab-hyperCVAD); FCM (fludarabine, cyclophosphamide,mitoxantrone); R-FCM (rituximab, fludarabine, cyclophosphamide,mitoxantrone); bortezomib and rituximab; temsirolimus and rituximab;temsirolimus and Velcade®; Iodine-131 tositumomab (Bexxar®) and CHOP;CVP (cyclophosphamide, vincristine, prednisone); R-CVP (rituximab-CVP);ICE (iphosphamide, carboplatin, etoposide); R-ICE (rituximab-ICE); FCR(fludarabine, cyclophosphamide, rituximab); FR (fludarabine, rituximab);and D.T. PACE (dexamethasone, thalidomide, cisplatin, Adriamycin®,cyclophosphamide, etoposide).

Other examples of chemotherapy treatments (including standard orexperimental chemotherapies) are described below. In addition, treatmentof certain lymphomas is reviewed in Cheson, B. D., Leonard, J. P.,“Monoclonal Antibody Therapy for B-Cell Non-Hodgkin's Lymphoma” The NewEngland Journal of Medicine 2008, 359(6), p. 613-626; and Wierda, W. G.,“Current and Investigational Therapies for Patients with CLL” Hematology2006, p. 285-294. Lymphoma incidence patterns in the United States isprofiled in Morton, L. M., et al. “Lymphoma Incidence Patterns by WHOSubtype in the United States, 1992-2001” Blood 2006, 107(1), p. 265-276.

Examples of immunotherapeutic agents treating lymphoma or leukemiainclude, but are not limited to, rituximab (such as Rituxan),alemtuzumab (such as Campath, MabCampath), anti-CD19 antibodies,anti-CD20 antibodies, anti-CD39 antibodies, anti-MN-14 antibodies,anti-TRAIL, Anti-TRAIL DR4 and DR5 antibodies, anti-CD74 antibodies,apolizumab, bevacizumab, CHIR-12.12, epratuzumab (hLL2-anti-CD22humanized antibody), galiximab, ha20, ibritumomab tiuxetan, lumiliximab,milatuzumab, ofaturmumab, PRO131921, SGN-40, WT-1 analog peptidevaccine, WT1 126-134 peptide vaccine, tositumomab, autologous humantumor-derived HSPPC-96, and veltuzumab. Additional immunotherapy agentsincludes using cancer vaccines based upon the genetic makeup of anindividual patient's tumor, such as lymphoma vaccine example is GTOP-99(MyVax®).

Examples of chemotherapy agents for treating lymphoma or leukemiainclude aldesleukin, alvocidib, antineoplaston AS2-1, antineoplastonA10, anti-thymocyte globulin, amifostine trihydrate, aminocamptothecin,arsenic trioxide, beta alethine, Bcl-2 family protein inhibitor ABT-263,BMS-345541, bortezomib (Velcade®), bryostatin 1, busulfan, carboplatin,campath-1H, CC-5103, carmustine, caspofungin acetate, clofarabine,cisplatin, Cladribine (Leustarin), Chlorambucil (Leukeran), Curcumin,cyclosporine, Cyclophosphamide (Cyloxan, Endoxan, Endoxana, Cyclostin),cytarabine, denileukin diftitox, dexamethasone, DT PACE, docetaxel,dolastatin 10, Doxorubicin (Adriamycin®, Adriblastine), doxorubicinhydrochloride, enzastaurin, epoetin alfa, etoposide, Everolimus(RAD001), fenretinide, filgrastim, melphalan, mesna, Flavopiridol,Fludarabine (Fludara), Geldanamycin (17-AAG), ifosfamide, irinotecanhydrochloride, ixabepilone, Lenalidomide (Revlimid®, CC-5013),lymphokine-activated killer cells, melphalan, methotrexate, mitoxantronehydrochloride, motexafin gadolinium, mycophenolate mofetil, nelarabine,oblimersen (Genasnnse) Obatoclax (GXI 5-070), oblimersen, octreotideacetate, omega-3 fatty acids, oxaliplatin, paclitaxel, PD0332991,PEGylated liposomal doxorubicin hydrochloride, pegfilgrastim, Pentstatin(Nipent), perifosine, Prednisolone, Prednisone, R-roscovitine(Selicilib, CYC202), recombinant interferon alfa, recombinantinterleukin-12, recombinant interleukin-11, recombinant flt3 ligand,recombinant human thrombopoietin, rituximab, sargramostim, sildenafilcitrate, simvastatin, sirolimus, Styryl sulphones, tacrolimus,tanespimycin, Temsirolimus (CC1-779), Thalidomide, therapeuticallogeneic lymphocytes, thiotepa, tipifarnib, Velcade® (bortezomib orPS-341), Vincristine (Oncovin), vincristine sulfate, vinorelbineditartrate, Vorinostat (SAHA), vorinostat, and FR (fludarabine,rituximab), CHOP (cyclophosphamide, doxorubicin, vincristine,prednisone), CVP (cyclophosphamide, vincristine and prednisone), FCM(fludarabine, cyclophosphamide, mitoxantrone), FCR (fludarabine,cyclophosphamide, rituximab), hyperCVAD (hyperfractionatedcyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate,cytarabine), ICE (iphosphamide, carboplatin and etoposide), MCP(mitoxantrone, chlorambucil, and prednisolone), R-CHOP (rituximab plusCHOP), R-CVP (rituximab plus CVP), R-FCM (rituximab plus FCM), R-ICE(rituximab-ICE), and R-MCP (R-MCP).

The therapeutic treatments can be supplemented or combined with any ofthe abovementioned therapies with stem cell transplantation ortreatment. One example of modified approach is radioimmunotherapy,wherein a monoclonal antibody is combined with a radioisotope particle,such as indium In 111, yttrium Y 90, iodine I-131. Examples ofcombination therapies include, but are not limited to, Iodine-131tositumomab (Bexxar®), Yttrium-90 ibritumomab tiuxetan (Zevalin®),Bexxar® with CHOP.

Other therapeutic procedures include peripheral blood stem celltransplantation, autologous hematopoietic stem cell transplantation,autologous bone marrow transplantation, antibody therapy, biologicaltherapy, enzyme inhibitor therapy, total body irradiation, infusion ofstem cells, bone marrow ablation with stem cell support, invitro-treated peripheral blood stem cell transplantation, umbilical cordblood transplantation, immunoenzyme technique, pharmacological study,low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery,radiation therapy, and nonmyeloablative allogeneic hematopoietic stemcell transplantation.

Uses in Manufacturing of Drug Product

Provided are also a use of the polymorphs described herein in themanufacture of a drug product. The one or more of the polymorphic formsdescribed herein (e.g., one or more of polymorphic Forms I, II, III, IV,V, VI, VII, VIII, IX, X, XI, XII and XIII) may be used as anintermediate in the manufacturing process to produce the drug product.

In certain embodiments, Forms I to XIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneare used in the manufacture of an active pharmaceutical ingredient. Incertain embodiments, Form I of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis used in the manufacture of an active pharmaceutical ingredient. Incertain embodiments, Form II of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis used in the manufacture of an active pharmaceutical ingredient. Incertain embodiments, Form III of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis used in the manufacture of an active pharmaceutical ingredient. Incertain embodiments, Form IV of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis used in the manufacture of an active pharmaceutical ingredient. Incertain embodiments, Form V of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis used in the manufacture of an active pharmaceutical ingredient. Incertain embodiments, Form VI of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis used in the manufacture of an active pharmaceutical ingredient. Incertain embodiments, Form VII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis used in the manufacture of an active pharmaceutical ingredient. Incertain embodiments, Form VIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis used in the manufacture of an active pharmaceutical ingredient. Incertain embodiments, Form IX of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis used in the manufacture of an active pharmaceutical ingredient. Incertain embodiments, Form X of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis used in the manufacture of an active pharmaceutical ingredient. Incertain embodiments, Form XI of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis used in the manufacture of an active pharmaceutical ingredient. Incertain embodiments, Form XII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis used in the manufacture of an active pharmaceutical ingredient. Incertain embodiments, Form XIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneis used in the manufacture of an active pharmaceutical ingredient. Incertain embodiments, the active pharmaceutical ingredient is Idelalisib.

Articles of Manufacture and Kits

Compositions comprising one or more of the polymorphic forms describedherein (e.g., one or more of polymorphic Forms I to XIII of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneand formulated in one or more pharmaceutically acceptable carriers,excipients or other ingredients can be prepared, placed in anappropriate container, and labeled for treatment of an indicatedcondition. Accordingly, there also is contemplated an article ofmanufacture, such as a container comprising a dosage form of one or moreof the polymorphic forms described herein (e.g., one or more ofpolymorphic Forms I to XIII of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and a label containing instructions for use of the compound(S).

In some embodiments, the article of manufacture is a containercomprising a dosage form of one or more of the polymorphic formsdescribed herein (e.g., one or more of polymorphic Forms I to XIII of ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,and one or more pharmaceutically acceptable carriers, excipients orother ingredients. In one embodiment of the articles of manufacturedescribed herein, the dosage form is a tablet.

Kits also are contemplated. For example, a kit can comprise a dosageform of a pharmaceutical composition and a package insert containinginstructions for use of the composition in treatment of a medicalcondition. The instructions for use in the kit may be for treating aPI3K-mediated disorder, including, for example, a hematologicmalignancy. In certain embodiments, the instructions for use in the kitmay be for treating leukemia. In one embodiment, the instructions foruse in the kit may be for treating non-Hodgkin's lymphoma (NHL) orchronic lymphocytic leukemia (CLL).

In certain embodiments, conditions indicated on the label can include,for example, treatment of cancer. Conditions indicated on the label caninclude non-Hodgkin's lymphoma (NHL). In one embodiment, the conditionmay be indolent non-Hodgkin's lymphoma (iNHL). In another embodiment,the condition may be chronic lymphocytic leukemia (CLL). Otherconditions that may be indicated on the label include, for example,follicular lymphoma (FL); lymphoplastic lymphoma (LPL); Waldenströmmacroglobulinemia (WM); marginal zone lymphoma (MZL); and small celllymphocytic lymphoma (SLL).

In certain embodiments, the polymorphic and solvate forms describedherein may potentially exhibit improved properties. For example, incertain embodiments, the polymorphic and solvate forms described hereinmay potentially exhibit improved stability. Such improved stabilitycould have a potentially beneficial impact on the manufacture of theCompound of Formula I, such as for example offering the ability to storeprocess intermediate for extended periods of time. Improved stabilitycould also potentially benefit a composition or pharmaceuticalcomposition of the Compound of Formula I. In certain embodiments, thepolymorphic and solvate forms described herein may also potentiallyresult in improved yield of the Compound of Formula I, or potentiallyresult in an improvement of the quality of the Compound of Formula I. Incertain embodiments, the polymorphic and solvate forms described hereinmay also exhibit improved pharmacokinetic properties and/or potentiallyimproved bioavailability.

EXAMPLES

The following examples are provided to further aid in understanding theembodiments disclosed in the application, and presuppose anunderstanding of conventional methods well known to those persons havingordinary skill in the art to which the examples pertain. The particularmaterials and conditions described hereunder are intended to exemplifyparticular aspects of embodiments disclosed herein and should not beconstrued to limit the reasonable scope thereof.

The polymorphic forms of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewere characterized by various analytical techniques, including X-raypowder diffraction pattern (XPPD), differential scanning calorimetry(DSC), and thermographic analysis (TGA) using the procedures describedbelow.

X-Ray Powder Diffraction:

XRPD patterns were collected at room temperature, using a PANalyticalX'Pert MPD Pro Powder X-Ray Diffractometer configured with reflectancestage with spinning, data acquisition range: 2-40 degrees 2θ, Copper(Cu) anode; Kα1/Kα2 radiation; tube current 40 mA; tube tension 45 kV;automatic divergence and anti-scatter slits. Samples were prepared foranalysis by distributing solid material as a thin layer on a siliconholder. Each holder was mounted on a reflectance/transmittance stage androtated during data acquisition.

Differential Scanning Calorimetry:

DSC was performed using a TA Instruments Q2000 DSC instrument. Thesample was placed into an aluminum DSC pan, and the weight accuratelyrecorded. The pan was covered with a lid, and then either crimped orhermetically sealed. The same cell was heated under a nitrogen purge ata rate of 10° C./min, up to a final temperature of 300° C. Indium wasused as the calibration standard.

Thermogravimetric Analysis:

TGA was performed using a TA Instruments Q5000 TGA instrument. Eachsample was placed in an aluminum sample pan and inserted into the TGfurnace. The furnace was heated under nitrogen at a rate of 10° C./min,up to a final temperature of 300° C. The TGA furnace was calibratedusing the magnetic Curie point method.

Example 1 Preparation of Form I of the HCl Salt of the Compound ofFormula (I)

This Example demonstrates exemplary methods to synthesize ahydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(the compound of Formula (I)).

Method A

In a vessel was charged 10.0 grams(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneand 50 mL absolute ethanol. In a separate vessel 1 mL of 12 M HCl (0.5equiv.) was diluted in 20 mL absolute ethanol. The acidified ethanol wasadded to the vessel containing the(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onesuspension while stirring. After a few minutes the suspension was seededwith <1 mL of polymorphic Form I of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onesuspension. The seeds were prepared by adding ethanol to amorphoussolids, thereby allowing the conversion of amorphous solids tocrystalline solid. The crystalline solids were then air dried. XRPD wasused to monitor progress in converting to the HCl salt. Additional 1 mLof 12 M HCl (0.5 equiv.) was charged after about 24 hours. After 14days, the XRPD confirmed full conversion to the HCl salt. The suspensionwas stored at ambient temperature for 30 days and solids were isolatedby filtration. The solids were washed one time with about 50 mL waterand allowed to air dry at room temperature.

KF of the resulting hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onewas observed to be about 13% and about 16% (avg. about 15%). DSC of theresulting hydrochloride salt (as seen in FIG. 1B) shows two broadendothermic events, one beginning at about 48° C. and the other at about184° C. No exothermic events were observed to be present. TGA of theresulting hydrochloride salt (as seen in FIG. 1C) shows two mass lossevents, one beginning at about 25° C. and ending at about 50° C., theother beginning at about 125° C. and ending (for the most part) at about200° C. DVS of the resulting hydrochloride salt (as seen in FIGS. 1D and1E) showed minor mass increase as a function of RH at 25° C. A singlecrystal X-ray of crystals grown from the resulting hydrochloride saltfiltrate was taken, and the data is summarized in Table 9 below. TheSingle Crystal X-Ray Crystallography data showed that the crystals are achannel solvate and a mono-HCl salt. Data from further characterizationof the crystals are summarized in Table 10 below.

TABLE 9 Single Crystal X-Ray Crystallography Data for the Compound ofFormula (I) Unit Cell Dimensions Form and Composition Distance (Å) Angle(°) Form water solvent API:water:solvent a b c α β γ Form I N Methanol1:1:0.5 31.102 (15) 9.166 (5) 19.738 (10) 90 125.948 (17) 90

TABLE 10 Crystal Data and Structure Refinement for the Compound ofFormula (I) Property Value Empirical formula C22.50 H18 Cl F N7 O1.50Formula weight 464.89 Temperature 100(2) K Wavelength 0.71073 Å Crystalsystem Monoclinic Space group C2 Volume 4555(4) Å³ Z 8 Density(calculated) 1.356 g/cm³Method B

To a slurry of5-fluoro-3-phenyl-2-((1S)-1-((9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)amino)propyl)quinazolin-4(3H)-one(18 g contains about 30% TEA HCl) in ethanol (30 g), concentratedhydrochloric acid (5.0 g, 1.6 mole eq.) was added maintainingtemperature ≦30° C. Immediately upon addition completion, high puritywater (15.0 g) was added to the solution. After adjusting the contentsto about 19 to 25° C. and checking the pH (targeting a value of ≦2.0,adding more concentrated hydrochloric acid if needed), the solution wasagitated for about 1 h at about 19 to 25° C. To slightly increase thesubstrate concentration,(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(in free form) (0.4 g) was charged portion-wise at about 19 to 25° C. Acloudy mixture was observed, which turned into a suspension after 30min. The resulting slurry was agitated at about 19 to 25° C. for about 5h and filtered. The wet cake was washed with cold EtOH (8.0 g, about 9°C.) and dried under vacuum at about 50° C.(S)-2-(1-(9H-Purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onehydrochloride was obtained as a solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.62(d, 2H), 7.85 (m, 1H), 7.70-7.40 (m, 6H), 7.30 (m, 1H), 4.67 (br, 1H),2.10 (m, 1H), 1.90 (m, 1H), 0.85 (t, 3H).

Example 2 Hydrate Screen on the HCl Salt of the Compound of Formula (I)

This Example demonstrates the effect of water on the stability ofpolymorphic Form I of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.

Polymorphic Form I of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,i.e., Compound of Formula (I), prepared according to the protocolsdescribed in Example 1 above was mixed with ethanol and water. Theamount of hydrochloride salt (Form I) and the ethanol/water ratiosummarized in Table 11 below. XRPDs were taken on Days 5 and 21. Resultsfrom this Example are summarized in Table 11 below.

TABLE 11 Results from hydrate screen on the HCl salt of the Compound ofFormula I Form I HCl salt of Ethanol/ Compound of water solubility XRPDafter solubility XRPD after Formula (I) (mg) a_(w) (mg/mL) 5 days(mg/mL) 21 days 98 0.2 26 Form I 60 Form I 114 0.3 47 Form I 33 Form I112 0.4 57 Form I 66 Form I 112 0.5 72 Form I 93 Form I 107 0.6 NA FormI 183 Form I 127 0.7 NA Form I 223 Form I 118 0.8 NA Form I 174 Form I113 0.9 NA Form I & 44 Form I & Form I of the Form I of the free form offree form of Compound of Compound of Formula (I) Formula (I)

The hydrate screen in the water/ethanol system showed no changes in XRPDexcept in the case of water activity 0.9, which converted some of thehydrochloride salt to polymorphic Form I of the free form of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,i.e., Compound of Formula (I).

Example 3 Form Screen on the HCl Salt of the Compound of Formula (I)

This Example demonstrates the conversion of polymorphic Form I of thehydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,i.e., the Compound of Formula (I), into other polymorphic forms based onparticular solvents used.

Polymorphic Form I of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,i.e., Compound of Formula (I), prepared according to the protocolsdescribed in Example 1 above was mixed with the solvent (as listed inTable 12 below) in a vial/flask, resulting in a suspension. The amountof hydrochloride salt (Form I) is also listed in Table 12 below.

After 7 days, a sample of the suspension was removed from thevial/flask, and the sample was centrifuged and filtered to separate thesolids from the liquid in the sample. The isolated solids werecharacterized by XRPD (collected at room temperature). The filtrate wasretained.

For several experiments, including the experiments involving THF,acetone and 2-MeTHF, crystals large enough for Single Crystal X-RayCrystallography were observed in the vial/flask. A sample of thecrystals taken in suspension was removed and analyzed by Single CrystalX-Ray Crystallography (data acquired at 100K).

After about 25 days, another sample was removed from the vial/flask, andthe sample was centrifuged and filtered to separate the solids from theliquid in the sample. The isolated solids were characterized by XRPD(collected at room temperature). Results from this Example aresummarized in Table 12 below.

TABLE 12 Results from form screen on the HCl salt of the Compound ofFormula I Single Crystal Form I HCl salt X-Ray of of Compound of XRPDafter XRPD after crystals from Formula (I) Solvent 7 days about 25suspension 119 mg water Form I Form I NA 117 mg isopropyl acetate (IPAc)Form I Form I NA 150 mg methyl t-butyl ether (MTBE) Form I Form I NA 132mg 2-propanol Form I mixture NA 160 mg dichloromethane (DCM) new FormVIII NA 163 mg n-heptane Form I Form I NA 114 mg tetrahydrofuran (THF)new Form IX IV 125 mg acetone new Form X II 155 mg methanol Form I FormI NA 120 mg acetonitrile (ACN) Form I Form I NA 157 mg Ethanol Form IForm I NA 140 mg ethyl acetate (EtOAc) Form I Form I NA 154 mg2-methyltetrahydrofuran (2-MeTHF) Form V Form V III 149 mg methyl ethylketone (MEK) new Form VII NA 176 mg methyl isobutyl ketone (MIBK) Form IForm VI NA 10 g  1-propanol 1-propanol solvate Form XII NA 10 g 2-propanol 1-propanol solvate Form XI NA 10 g  1-butanol 1-butanolsolvate Form XIII NA

The XRPDs taken for polymorphic Forms II-XIII are provided in FIGS.2-13, respectively. Single Crystal X-Ray Crystallography data werecollected from polymorphic Forms II-IV and XII prepared in this Example,and such data is summarized in Table 13 below.

TABLE 13 Single Crystal X-Ray Crystallography Data Unit Cell DimensionsForm and Composition Distance (Å) Angle (°) Form solventAPI:water:solvent a b c α β γ II acetone 1:0:3 13.266 (3) 13.858 (3)31.012 (6) 90 90 90 III 2MeTHF 1:1:1.5 25.077 (3)  9.1485 (10) 14.2476(14) 90 110.967 (3) 90 IV THF 1:0:3 13.4685 (6)  13.8415 (6)  31.7543(14) 90 90 90 XII 1-propanol 1:0:1 10.717 (3) 10.161 (3) 12.409 (4) 90104.021 (4) 90

Example 4 Solvent Screen on Form I of the HCl Salt of the Compound ofFormula (I)

This Example demonstrates the preparation of solvated forms ofpolymorphic Form I of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,i.e., the Compound of Formula (I).

Polymorphic Form I of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,i.e., Compound of Formula (I) was prepared by suspending 5 g of the freebase Form I of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-onein 25 mL absolute ethanol. The sample was agitated at 200 rpm and about23° C. 1.05 mL of 12M HCl (1.1 eq.) was diluted in 10 mL absoluteethanol, then added to the suspension of the Compound of Formula (I) inethanol, forming a slurry. The slurry suspension was stirred at about23° C. for about 24 hours, filtered and washed with 10 mL absoluteethanol and dried under vacuum for three days. Formation of thepolymorphic Form I of a hydrochloride salt of the Compound of Formula(I) was confirmed by x-ray powder diffraction.

50 mg of the polymorphic Form I of a hydrochloride salt of the Compoundof Formula (I) prepared according to the protocols described above wasmixed with increasing amounts of each solvent listed in Table 14 below(10 vol, 20 vol, 30 vol, 40 vol, 50 vol, 60 vol, 70 vol, 70 vol (atabout 50° C.)) until the material dissolved or reached the maximumamount of solvent. The mixtures were then evaluated for identificationof the solid form using the following screening procedures:

Maturation: The suspensions were cycled in a platform shaker incubatorbetween about 50° C. and room temperature (8 hours per cycle, for threedays);

Slurry at 5° C.: 50 mg of the polymorphic Form I of a hydrochloride saltof the Compound of Formula (I) was suspended in 40 vol of the solvent.The suspensions were left stirring at about 5° C. for about 7 days;

Slurry at 50° C.: 50 mg of the polymorphic Form I of a hydrochloridesalt of the Compound of Formula (I) was suspended in 40 vol of thesolvent. The suspensions were left stirring at about 50° C. for about 2days;

Salt formation: 50 mg of the polymorphic Form I of a hydrochloride saltof the Compound of Formula (I) was dissolved or suspended in 10 vol ofsolvent and held at about 50° C. for 15 minutes, after which 1.1 eq ofHCl (11.6 μL of 12M HCl) were added and the sample was slowly cooled toabout 5° C. at about 0.1° C. per minute;Solvent deposition: 25 mg of the polymorphic Form I of a hydrochloridesalt of the Compound of Formula (I) was transferred to a 2 mL vial,which was then placed into a larger sealed vial with 3 mL of thecorresponding solvent, then held at about 40° C. for about 13 days.

Any solids obtained from the above screening procedures were analyzedwet/damp by XRPD as described below. The solids were isolated bydecanting and/or filtration, then dried under vacuum. Solid form samplesobtained after maturation experiments were dried under vacuum andanalyzed by NMR to determine if the solvating ethanol was replaced bythe suspending solvent. As shown in Table 14, the screening experimentsidentified new solvated forms of the HC salt of the Compound of FormulaI. For Patterns 1, 2, 3, and 4, each of the four of the identifiedsolvated forms are a family of solvates, which are observed from morethan one solvent.

TABLE 14 Results from solvent screen on Form I of the HCl salt of theCompound of Formula I Form Solvent Represenative XRPD Pattern 1 EthylAcetate FIG. 14A (damp) Propyl acetate FIG. 14B (dry) Pattern 21-Methyl-1-propanol FIG. 15A Isopropyl acetate Pattern 31,2-Dimethyoxyethane FIG. 16A 1,4-Dioxane Acetone Acetone:WaterAcetonitrile Chloroform Dicholoromethane Diethyl ether Ethyl acetate MEKMIBK Nitromethane Propyl acetate Tetrahydrofuran Toluene Pattern 41-Propanol FIG. 17A 2-Propanol IPA:Water (5%) 2-Methyl-1-propanol2-Methyl-1-propanol FIG. 18A solvate 1,4-Dioxane solvate 1,4-DioxaneFIG. 19A Toluene solvate Toluene FIG. 20

Representative samples of the solvate forms listed in Table 14 obtainedfrom the crystallization screening were dried under vacuum and furthercharacterized. The data from these further characterization experimentsis summarized in Table 15.

TABLE 15 Results from solvent screen on Form I of the HCl salt of theCompound of Formula I Form Solvent NMR of dry DSC TGA Pattern 1Propylacetate n/t n/t n/t Pattern 2 Isopropyl acetate 0.56eq iPrOAc  68°C. (−42 J/g)  9.7% (40° C.-130° C.) 153° C. (−38 J/g)  4.7% (130°C.-230° C.) 179° C. (−32 J/g) Pattern 3 1,2-Dimethyoxyethane 0.93eq DME172° C. (−92 J/g) 10.7% (110° C.-245°C.) Pattern 4 Isopropyl alcohol0.98eq IPA 170° C. (−192 J/g) 13.4% (130° C.-215° C.)2-Methyl-1-propanol 2-Methyl-1-propanol 1.34eq 2-Methyl-1- 113° C. (−134J/g) 19.0% (90° C.-225° C.) solvate propanol 1,4-Dioxane solvate1,4-Dioxane 0.65eq 1.4-Dioxane 158° C. (−96 J/g) 12.7% (80° C.-225° C.)Toluene solvate Toluene n/t n/t n/t n/t: not testedX-Ray Powder Diffraction (XRPD)

Two methods were used to collect XRPD on the samples described above.

Bruker AXS C2 GADDS

X-Ray Powder Diffraction patterns were collected on a Bruker AXS C2GADDS diffractometer using Cu Kα radiation (40 kV, 40 mA), automated XYZstage, laser video microscope for auto-sample positioning and a HiStar2-dimensional area detector. X-ray optics consists of a single Göbelmultilayer mirror coupled with a pinhole collimator of 0.3 mm.

The beam divergence, i.e. the effective size of the X-ray beam on thesample, was approximately 4 mm. A θ-θ continuous scan mode was employedwith a sample-detector distance of 20 cm which gives an effective 2θrange of 3.2°-29.7°. Typically the sample would be exposed to the X-raybeam for 120 seconds. The software used for data collection was GADDSfor XP/2000 4.1.43 and the data were analysed and presented usingDiffrac Plus EVA v13.0.0.2 or v15.0.0.0.

Ambient conditions: Samples run under ambient conditions were preparedas flat plate specimens using powder as received without grinding.Approximately 1-2 mg of the sample was lightly pressed on a glass slideto obtain a flat surface.

Non-ambient conditions: Samples run under non-ambient conditions weremounted on a silicon wafer with heat-conducting compound. The sample wasthen heated to the appropriate temperature at 50° C./min andsubsequently held isothermally for up to 4 minutes before datacollection was initiated.

Bruker AXS D8 Advance

X-Ray Powder Diffraction patterns were collected on a Bruker D8diffractometer using Cu Kα radiation (40 kV, 40 mA), 0-20 goniometer,and divergence of V4 and receiving slits, a Ge monochromator and aLynxeye detector. The software used for data collection was Diffrac PlusXRD Commander v2.6.1 and the data were analysed and presented usingDiffrac Plus EVA v13.0.0.2 or v15.0.0.0.

Samples were run under ambient conditions as flat plate specimens usingpowder as received. The sample was gently packed into a cavity cut intopolished, zero-background (510) silicon wafer. The sample was rotated inits own plane during analysis. The details of the data collection are:angular range: 2 to 42°2θ, step size: 0.05°2θ, collection time: 0.5s/step.

Nuclear Magnetic Resonance (NMR)

¹H-NMR spectra were collected on a Bruker 400 MHz instrument equippedwith an autosampler and controlled by a DRX400 console. Automatedexperiments were acquired using ICON-NMR v4.0.7 running with Topspinv1.3 using the standard Bruker loaded experiments. For non-routinespectroscopy, data were acquired through the use of Topspin alone.

Samples were prepared in DMSO-d6, unless otherwise stated. Off-lineanalysis was carried out using ACD Labs 2012 release (build 61851).

Differential Scanning Calorimetry (DSC)

DSC data were collected on a Mettler DSC 823E equipped with a 34position auto-sampler. The instrument was calibrated for energy andtemperature using certified indium. Typically 0.5-4 mg of each sample,in a pin-holed aluminium pan, was heated at 10° C./min from 25° C. to350° C. A nitrogen purge at 50 ml/min was maintained over the sample.

The instrument control and data analysis software was STARe v9.20.

Thermo-Gravimetric Analysis (TGA) TGA data were collected on a MettlerTGA/SDTA 851e equipped with a 34 position autosampler. The instrumentwas temperature calibrated using certified indium. Typically 2-13 mg ofeach sample was loaded onto a pre-weighed aluminium crucible and washeated at 10° C./min from ambient temperature to 350° C. A nitrogenpurge at 50 ml/min was maintained over the sample.

The instrument control and data analysis software was STARe v9.20.

The XRPDs taken for the solvate forms identified in Table 14 areprovided in FIGS. 14A, 14B, 15A, 16A, 17A, 18A, 29A, and 20respectively.

For Pattern 1, shown in FIGS. 14A and 15B, 50 mg of the hydrochloridesalt of the Compound of Formula (I) was suspended in propyl acetate (3.5mL, 70 vol) and held at 50° C. for 15 minutes, after which 1.1 eq of 12MHCl (11.6 μL) was added and the sample slowly cooled from 50° C. to 5°C. at 0.1° C. per minute. The XRPD pattern shown in FIG. 14A wasobserved while the sample was wet. On drying in a vacuum oven at about25° C. for 6 days, the sample was converted to the XRPD pattern shown inFIG. 14B (Pattern 9). NMR data confirm the presence of propyl acetate inthe crystallized from. FIG. 14C depicts the XRPD pattern after furtherheating at about 145° C. for about 16 hours (Pattern 9′). Table 16 liststhe XRPD peaks for Pattern 9′

TABLE 16 XRPD Peak List for Pattern 9′ Form Angle (2-Theta °) Intensity(%) 7.5 11.1 9.2 100.0 11.8 16.8 12.0 12.4 14.1 19.5 16.8 31.3 17.1 18.818.5 32.6 19.4 8.2 20.1 9.0 20.8 12.4 21.5 11.2 22.9 20.7 23.4 32.5 24.712.2 25.9 28.7 28.0 17.7 28.6 10.9 29.2 5.9 29.5 5.6

For Pattern 2, shown in FIG. 15A, 50 mg of the polymorphic Form I of ahydrochloride salt of the Compound of Formula (I) was treated withisopropyl acetate (3.5 mL, 70 vols) producing a suspension at 50° C.This suspension was matured between 50° C. and room temperature (8 hoursper cycle) for three days. ¹H NMR data confirm the presence of isopropylacetate in the crystallized from.

For Pattern 3, shown in FIG. 16A, 50 mg of the polymorphic Form I of ahydrochloride salt of the Compound of Formula (I) was treated with1,2-dimethoxyethane (3.5 mL, 70 vols) producing a suspension at 50° C.This suspension was matured between 50° C. and room temperature (8 hoursper cycle) for three days. ¹H NMR data confirm the presence of1,2-dimethoxyethane in the crystallized from.

For Pattern 4, shown in FIG. 17A, 50 mg of the polymorphic Form I of ahydrochloride salt of the Compound of Formula (I) was treated with2-propanol (3.5 mL, 70 vols), producing a suspension at 50° C. Thissuspension was matured between 50° C. and room temperature (8 hours percycle) for three days. ¹H NMR data confirm the presence of 2-propanol inthe crystallized from.

For the 2-Methyl-1-propanol solvate, shown in FIG. 18A, 50 mg of thepolymorphic Form I of a hydrochloride salt of the Compound of Formula(I) was treated with 2-methyl-1-propanol (3.5 mL, 70 vols), producing asuspension at 50° C. This suspension was matured between 50° C. and roomtemperature (8 hours per cycle) for three days. FIG. 18D depicts thesame XRPD diffractogram, showing the entire Y axis (i.e., nottruncated). ¹H NMR data confirm the presence of 2-methyl-1-propanol inthe crystallized from.

For the 1,4-Dioxane solvate, shown in FIG. 19A, 50 mg of the polymorphicForm I of a hydrochloride salt of the Compound of Formula (I) wastreated with 1,4-dioxane (3.5 mL, 70 vols), producing a suspension at50° C. This suspension was matured between 50° C. and room temperature(8 hours per cycle) for three days. The XRPD pattern is shown in FIG.20. ¹H NMR data confirm the presence of 1,4-dioxane in the crystallizedfrom.

For the toluene solvate, shown in FIG. 20 (wet), 50 mg of thepolymorphic Form I of a hydrochloride salt of the Compound of Formula(I) was treated with toluene (3.5 mL, 70 vols), producing a suspensionat 50° C. This suspension was matured between 50° C. and roomtemperature (8 hours per cycle) for three days. Upon drying, the XRPD ofthe toluene solvent is a mixture of Pattern 1 and Pattern 9′.

DSC plots for Pattern 9, Pattern 2, Pattern 3, Pattern 4, the2-Methyl-1-propanol solvate form, and the 1,4-dioxane solvate formidentified in Table 14 are provided in FIGS. 14D, 15B, 16B, 17B, 18B,and 19B respectively. TGA plots for Pattern 9, Pattern 2, Pattern 3,Pattern 4, the 2-Methyl-1-propanol solvate form, and the 1,4-dioxanesolvate form identified in Table 14 are provided in FIGS. 14E, 15C, 16C,17C, 18C, and 19C, respectively.

What is claimed is:
 1. A polymorph of a hydrochloride salt of a compoundof Formula (I):

wherein the polymorph is selected from the group consisting of Form I,Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, FormXII, and Form XIII; and wherein: Form I has an X-ray diffraction patterncomprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 11.6,16.6, 18.2, 23.2 and 25.1; Form V has an X-ray diffraction patterncomprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 15.9,24.0, 25.6 and 28.1; Form VI has an X-ray diffraction pattern comprisingdegree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 11.8, 17.0, 23.2and 25.1; Form VII has an X-ray diffraction pattern comprising degree2θ-reflections, plus or minus 0.2 degrees 2θ, at 9.8, 17.8, 21.7 and24.0; Form VIII has an X-ray diffraction pattern comprising degree2θ-reflections, plus or minus 0.2 degrees 2θ, at 10.0, 19.9, 21.7 and24.1; Form IX has an X-ray diffraction pattern comprising degree2θ-reflections, plus or minus 0.2 degrees 2θ, at 9.8, 19.6, 21.8 and24.0; Form X has an X-ray diffraction pattern comprising degree2θ-reflections, plus or minus 0.2 degrees 2θ, at 9.9, 21.8, and 24.2;Form XI has an X-ray diffraction pattern comprising degree2θ-reflections, plus or minus 0.2 degrees 2θ, at 12.5, 17.0, 19.3, 20.3,22.0 and 25.5; Form XII has an X-ray diffraction pattern comprisingdegree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 7.4, 12.4, 16.9and 25.4; and Form XIII has an X-ray diffraction pattern comprisingdegree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 6.9, 16.8, 18.5and 23.9.
 2. The polymorph of claim 1, wherein the polymorph is selectedfrom the group consisting of Form I, Form V, Form VI, Form VII, FormVIII, Form IX, Form X, Form XI, Form XII, and Form XIII; and wherein:Form I has an X-ray diffraction pattern comprising degree2θ-reflections, plus or minus 0.2 degrees 2θ, at 8.9, 11.6, 13.8, 16.6,18.2, 19.4, 22.5, 23.2 and 25.1; Form V has an X-ray diffraction patterncomprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 8.0,15.9, 18.9, 20.3, 24.0, 25.6, 28.1 and 36.3; Form VI has an X-raydiffraction pattern comprising degree 2θ-reflections, plus or minus 0.2degrees 2θ, at 11.8, 13.9, 16.7, 17.0, 19.9, 22.3, 22.5, 23.2 and 25.1;Form VII has an X-ray diffraction pattern comprising degree2θ-reflections, plus or minus 0.2 degrees 2θ, at 6.0, 9.8, 11.9, 15.3,19.7, 20.1, 21.7, 24.0, 28.4 and 28.9; Form VIII has an X-raydiffraction pattern comprising degree 2θ-reflections, plus or minus 0.2degrees 2θ, at 10.0, 12.4, 15.3, 19.0, 19.9, 20.3, 21.7, 24.1 and 28.9;Form IX has an X-ray diffraction pattern comprising degree2θ-reflections, plus or minus 0.2 degrees 2θ, at 9.5, 9.8, 12.5, 19.6,20.8, 21.8, 24.0 and 29.0; Form X has an X-ray diffraction patterncomprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 9.9,11.9, 15.5, 19.4, 19.8, 20.3, 21.8, 24.2, 28.6 and 29.0; Form XI has anX-ray diffraction pattern comprising degree 2θ-reflections, plus orminus 0.2 degrees 2θ, at 7.4, 12.5, 15.0, 17.0, 19.3, 20.3, 22.0, 25.5and 31.7; Form XII has an X-ray diffraction pattern comprising degree2θ-reflections, plus or minus 0.2 degrees 2θ, at 7.4, 12.4, 16.9, 19.1,19.6, 23.3, 24.9, 25.4 and 29.4; and Form XIII has an X-ray diffractionpattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ,at 6.9, 8.0, 8.1, 9.7, 11.7, 13.6, 16.8, 18.5, 23.5, 23.9 and 25.7.
 3. Apolymorph of a hydrochloride salt of a compound of Formula (I):

wherein the polymorph is selected from the group consisting of Form I,Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, FormIX, Form X, Form XI, Form XII, and Form XIII; and wherein: Form I has anX-ray diffraction pattern as shown in FIG. 1; Form II has a calculatedX-ray diffraction pattern as shown in FIG. 2; Form III has a calculatedX-ray diffraction pattern as shown in FIG. 3; Form IV has a calculatedX-ray diffraction pattern as shown in FIG. 4; Form V has an X-raydiffraction pattern as shown in FIG. 5; Form VI has an X-ray diffractionpattern as shown in FIG. 6; Form VII has an X-ray diffraction pattern asshown in FIG. 7; Form VIII has an X-ray diffraction pattern as shown inFIG. 8; Form IX has an X-ray diffraction pattern as shown in FIG. 9;Form X has an X-ray diffraction pattern as shown in FIG. 10; Form XI hasan X-ray diffraction pattern as shown in FIG. 11; Form XII has an X-raydiffraction pattern as shown in FIG. 12; and Form XIII has an X-raydiffraction pattern as shown in FIG.
 13. 4. A polymorph of ahydrochloride salt of a compound of Formula (I):

wherein the polymorph is selected from the group consisting of Form I,Form II, Form III, Form IV and Form XII; and wherein: Form I has a unitcell, as determined by crystal X-ray crystallography, of the followingdimensions: a=31.102 (15) Å; b=9.166 (5) Å; c=19.738 (10) Å; α=90°;β=125.948(17°); and γ=90°; Form II has a unit cell, as determined bycrystal X-ray crystallography, of the following dimensions: a=13.266 (3)Å; b=13.858 (3) Å; c=31.012 (6) Å; α=90°; β=90°; and γ=90°; Form III hasa unit cell, as determined by crystal X-ray crystallography, of thefollowing dimensions: a=25.077 (3) Å; b=9.149 (10) Å; c=14.248 (14) Å;α=90°; β=110.967 (3°); and γ=90°; Form IV has a unit cell, as determinedby crystal X-ray crystallography, of the following dimensions: a=13.469(6) Å; b=13.842 (6) Å; c=31.754 (14) Å; α=90°; β=90°; and γ=90°; andForm XII has a unit cell, as determined by crystal X-raycrystallography, of the following dimensions: a=10.717 (3); b=10.161(3); c=12.409 (4); α=90; β=104.021 (4); and γ=90.
 5. The polymorph ofclaim 1, wherein the polymorph is Form I.
 6. The polymorph of claim 3,wherein the polymorph is Form II.
 7. The polymorph of claim 3, whereinthe polymorph is Form III.
 8. The polymorph of claim 3, wherein thepolymorph is Form IV.
 9. The polymorph of claim 1, wherein the polymorphis Form V.
 10. The polymorph of claim 1, wherein the polymorph is FormVI.
 11. The polymorph of claim 1, wherein the polymorph is Form VII. 12.The polymorph of claim 1, wherein the polymorph is Form VIII.
 13. Thepolymorph of claim 1, wherein the polymorph is Form IX.
 14. Thepolymorph of claim 1, wherein the polymorph is Form X.
 15. The polymorphof claim 1, wherein the polymorph is Form XI.
 16. The polymorph of claim1, wherein the polymorph is Form XII.
 17. The polymorph of claim 1,wherein the polymorph is Form XIII.
 18. A composition produced by:combining a compound of Formula (I):

with hydrochloric acid and a solvent to produce the compositioncomprising one or more polymorphs of a hydrochloride salt of thecompound of Formula (I); or combining a hydrochloride salt of thecompound of Formula (I) with a solvent to produce the compositioncomprising one or more polymorphs of a hydrochloride salt of thecompound of Formula (I), wherein the solvent is selected from the groupconsisting of methanol, ethanol, water, isopropyl acetate, ethylacetate, methyl tert-butyl ether, n-heptane, acetonitrile, acetone,2-methyltetrahydrofuran, tetrahydrofuran, methyl isobutyl ketone, methylethyl ketone, dichloromethane, 2-propanol, 1-propanol, 1-butanol, andany mixtures thereof, and wherein the one or more polymorphs areselected from the group consisting of Form I, Form V, Form VI, Form VII,Form VIII, Form IX, Form X, Form XI, Form XII, and Form XIII; andwherein: Form I has an X-ray diffraction pattern comprising degree2θ-reflections, plus or minus 0.2 degrees 2θ, at 11.6, 16.6, 18.2, 23.2and 25.1; Form V has an X-ray diffraction pattern comprising degree2θ-reflections, plus or minus 0.2 degrees 2θ, at 15.9, 24.0, 25.6 and28.1; Form VI has an X-ray diffraction pattern comprising degree2θ-reflections, plus or minus 0.2 degrees 2θ, at 11.8, 17.0, 23.2 and25.1; Form VII has an X-ray diffraction pattern comprising degree2θ-reflections, plus or minus 0.2 degrees 2θ, at 9.8, 17.8, 21.7 and24.0; Form VIII has an X-ray diffraction pattern comprising degree2θ-reflections, plus or minus 0.2 degrees 2θ, at 10.0, 19.9, 21.7 and24.1; Form IX has an X-ray diffraction pattern comprising degree2θ-reflections, plus or minus 0.2 degrees 2θ, at 9.8, 19.6, 21.8 and24.0; Form X has an X-ray diffraction pattern comprising degree2θ-reflections, plus or minus 0.2 degrees 2θ, at 9.9, 21.8, and 24.2;Form XI has an X-ray diffraction pattern comprising degree2θ-reflections, plus or minus 0.2 degrees 2θ, at 12.5, 17.0, 19.3, 20.3,22.0 and 25.5; Form XII has an X-ray diffraction pattern comprisingdegree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 7.4, 12.4, 16.9and 25.4; and Form XIII has an X-ray diffraction pattern comprisingdegree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 6.9, 16.8, 18.5and 23.9.
 19. The composition of claim 18, wherein: the one or morepolymorphs is Form I; and the solvent is selected from the groupconsisting of methanol, ethanol, water, isopropyl acetate, ethylacetate, methyl tert-butyl ether, n-heptane, acetonitrile, and anymixtures thereof.
 20. The composition of claim 18, wherein: the one ormore polymorphs is Form II or Form X, or a mixture thereof; and thesolvent is acetone.
 21. The composition of claim 18, wherein: the one ormore polymorphs is Form III or Form V, or a mixture thereof; and thesolvent is 2-methyltetrahydrofuran.
 22. The composition of claim 18,wherein: the one or more polymorphs is Form IV or Form IX, or a mixturethereof; and the solvent is tetrahydrofuran.
 23. The composition ofclaim 18, wherein: the one or more polymorphs is Form VI; and thesolvent is methyl isobutyl ketone.
 24. The composition of claim 18,wherein: the one or more polymorphs is Form VII; and the solvent ismethyl ethyl ketone.
 25. The composition of claim 18, wherein: the oneor more polymorphs is Form VIII; and the solvent is dichloromethane. 26.The composition of claim 18, wherein: the one or more polymorphs is FormXI; and the solvent is 2-propanol.
 27. The composition of claim 18,wherein: the one or more polymorphs is Form XII; and the solvent is1-propanol.
 28. The composition of claim 18, wherein: the one or morepolymorphs is Form XIII; and the solvent is 1-butanol.
 29. The polymorphof claim 1, wherein the hydrochloride salt is a monohydrochloride salt.30. A composition comprising one or more polymorphs of claim
 1. 31. Thecomposition of claim 30, wherein the one or more polymorphs are amixture of at least two polymorphs.
 32. The composition of claim 30,wherein the composition contains less than 95% by weight of substancesother than the one or more polymorphs.
 33. A pharmaceutical compositioncomprising the polymorph of claim 1, and one or more pharmaceuticallyacceptable carriers or excipients.
 34. The pharmaceutical composition ofclaim 33, wherein the pharmaceutical composition is a tablet.
 35. Amethod of treating a human in need of a treatment for cancer, comprisingadministering to the human a polymorph of claim 1, wherein the cancer isselected from the group consisting of chronic lymphocytic leukemia(CLL), indolent non-Hodgkin's lymphoma (iNHL), and refractory iNHL. 36.The method of claim 35, wherein the cancer is selected from smalllymphocytic lymphoma (SLL), and follicular B-cell non-Hodgin Lymphoma(FL).
 37. A method of producing a composition comprising one or morepolymorphs of a hydrochloride salt of a compound of Formula (I):

comprising: combining the compound of Formula (I) with hydrochloric acidand a solvent to produce the composition; or combining a hydrochloridesalt of the compound of Formula (I) with a solvent to produce thecomposition, wherein the solvent is selected from the group consistingof methanol, ethanol, water, isopropyl acetate, ethyl acetate, methyltert-butyl ether, n-heptane, acetonitrile, acetone,2-methyltetrahydrofuran, tetrahydrofuran, methyl isobutyl ketone, methylethyl ketone, dichloromethane, 2-propanol, 1-propanol, 1-butanol, andany mixtures thereof, and wherein the one or more polymorphs areselected from the group consisting of Form I, Form V, Form VI, Form VII,Form VIII, Form IX, Form X, Form XI, Form XII, and Form XIII; andwherein: Form I has an X-ray diffraction pattern comprising degree2θ-reflections, plus or minus 0.2 degrees 2θ, at 11.6, 16.6, 18.2, 23.2and 25.1; Form V has an X-ray diffraction pattern comprising degree2θ-reflections, plus or minus 0.2 degrees 2θ, at 15.9, 24.0, 25.6 and28.1; Form VI has an X-ray diffraction pattern comprising degree2θ-reflections, plus or minus 0.2 degrees 2θ, at 11.8, 17.0, 23.2 and25.1; Form VII has an X-ray diffraction pattern comprising degree2θ-reflections, plus or minus 0.2 degrees 2θ, at 9.8, 17.8, 21.7 and24.0; Form VIII has an X-ray diffraction pattern comprising degree2θ-reflections, plus or minus 0.2 degrees 2θ, at 10.0, 19.9, 21.7 and24.1; Form IX has an X-ray diffraction pattern comprising degree2θ-reflections, plus or minus 0.2 degrees 2θ, at 9.8, 19.6, 21.8 and24.0; Form X has an X-ray diffraction pattern comprising degree2θ-reflections, plus or minus 0.2 degrees 2θ, at 9.9, 21.8, and 24.2;Form XI has an X-ray diffraction pattern comprising degree2θ-reflections, plus or minus 0.2 degrees 2θ, at 12.5, 17.0, 19.3, 20.3,22.0 and 25.5; Form XII has an X-ray diffraction pattern comprisingdegree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 7.4, 12.4, 16.9and 25.4; and Form XIII has an X-ray diffraction pattern comprisingdegree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 6.9, 16.8, 18.5and 23.9.
 38. The method of claim 37, wherein: the one or morepolymorphs is Form I; and the solvent is selected from the groupconsisting of methanol, ethanol, water, isopropyl acetate, ethylacetate, methyl tert-butyl ether, n-heptane, acetonitrile, and anymixtures thereof.
 39. The method of claim 37, wherein: the one or morepolymorphs is Form II or Form X, or a mixture thereof; and the solventis acetone.
 40. The method of claim 37, wherein: the one or morepolymorphs is Form III or Form V, or a mixture thereof; and the solventis 2-methyltetrahydrofuran.
 41. The method of claim 37, wherein: the oneor more polymorphs is Form IV or Form IX, or a mixture thereof; and thesolvent is tetrahydrofuran.
 42. The method of claim 37, wherein: the oneor more polymorphs is Form VI; and the solvent is methyl isobutylketone.
 43. The method of claim 37, wherein: the one or more polymorphsis Form VII; and the solvent is methyl ethyl ketone.
 44. The method ofclaim 37, wherein: the one or more polymorphs is Form VIII; and thesolvent is dichloromethane.
 45. The method of claim 37, wherein: the oneor more polymorphs is Form XI; and the solvent is 2-propanol.
 46. Themethod of claim 37, wherein: the one or more polymorphs is Form XII; andthe solvent is 1-propanol.
 47. The method of claim 37, wherein: the oneor more polymorphs is Form XIII; and the solvent is 1-butanol.